U.S. patent application number 16/764489 was filed with the patent office on 2021-04-15 for compounds and pharmaceutical compositions thereof for use in the treatment of fibrotic diseases.
The applicant listed for this patent is Galapagos NV. Invention is credited to Reginald Christophe Xavier BRYS, Philippe CLEMENT-LACROIX, Steve Irma Joel DE VOS, Laurent Raymond Maurice SANIERE.
Application Number | 20210106582 16/764489 |
Document ID | / |
Family ID | 1000005312631 |
Filed Date | 2021-04-15 |
![](/patent/app/20210106582/US20210106582A1-20210415-C00001.png)
![](/patent/app/20210106582/US20210106582A1-20210415-C00002.png)
![](/patent/app/20210106582/US20210106582A1-20210415-C00003.png)
![](/patent/app/20210106582/US20210106582A1-20210415-C00004.png)
![](/patent/app/20210106582/US20210106582A1-20210415-C00005.png)
![](/patent/app/20210106582/US20210106582A1-20210415-C00006.png)
![](/patent/app/20210106582/US20210106582A1-20210415-C00007.png)
![](/patent/app/20210106582/US20210106582A1-20210415-C00008.png)
![](/patent/app/20210106582/US20210106582A1-20210415-C00009.png)
![](/patent/app/20210106582/US20210106582A1-20210415-C00010.png)
![](/patent/app/20210106582/US20210106582A1-20210415-C00011.png)
View All Diagrams
United States Patent
Application |
20210106582 |
Kind Code |
A1 |
BRYS; Reginald Christophe Xavier ;
et al. |
April 15, 2021 |
COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR USE IN THE
TREATMENT OF FIBROTIC DISEASES
Abstract
The present invention relates to compounds useful in the
prophylaxis and/or treatment of one or more fibrotic diseases. In
particular, the compounds of the invention antagonize GPR84, a
G-protein-coupled receptor. The present invention also provides
pharmaceutical compositions comprising the compounds for use and
methods for the prophylaxis and/or treatment of one or more
fibrotic diseases by administering said compound.
Inventors: |
BRYS; Reginald Christophe
Xavier; (Mechelen, BE) ; CLEMENT-LACROIX;
Philippe; (Romainville, FR) ; DE VOS; Steve Irma
Joel; (Mechelen, BE) ; SANIERE; Laurent Raymond
Maurice; (Romainville, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Galapagos NV |
Mechelen |
|
BE |
|
|
Family ID: |
1000005312631 |
Appl. No.: |
16/764489 |
Filed: |
November 15, 2018 |
PCT Filed: |
November 15, 2018 |
PCT NO: |
PCT/EP2018/081457 |
371 Date: |
May 15, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/519 20130101;
A61K 31/4375 20130101; A61K 31/496 20130101; A61P 1/16 20180101;
A61K 31/4412 20130101; A61P 11/00 20180101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 31/4375 20060101 A61K031/4375; A61P 1/16 20060101
A61P001/16; A61P 11/00 20060101 A61P011/00; A61K 31/496 20060101
A61K031/496; A61K 31/4412 20060101 A61K031/4412 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 15, 2017 |
GB |
1718838.4 |
Oct 25, 2018 |
GB |
1817346.8 |
Claims
1. A method for prophylaxis and/or treatment of one or more
fibrotic diseases comprising administering a GPR84 antagonist
activity to a subject in need thereof.
2. The method according to claim 1, wherein the compound is
according to formula I: ##STR00025## wherein R.sup.1 is H, Me, or
halo; L.sub.1 is absent or is --O--, --S--, or --NR.sup.4a--; G is
R.sup.2 --W-L.sub.2-R.sup.2, or --W-L.sub.3-R.sup.3; W is C.sub.1-4
alkylene, C.sub.2-4 alkenylene having one double bond, or C.sub.2-4
alkynylene having one triple bond; L.sub.2 is absent or is --O--;
R.sup.2 is H, C.sub.1-8 alkyl, optionally substituted with one to
three groups independently selected from OH, halo, CN, C.sub.1-6
alkoxy, C.sub.3-7 cycloalkyl, 4-6 membered heterocycloalkyl
comprising one to three heteroatoms independently selected from S,
and O, 5-6 membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O, and phenyl, C.sub.4-7
cycloalkenyl comprising one double bond, 5-7 membered
heterocycloalkenyl comprising one double bond, and one to three
heteroatoms independently selected from N, O, and S, C.sub.3-7
cycloalkyl optionally substituted with one or more independently
selected R.sup.5 groups, 4-10 membered heterocycloalkyl comprising
one to two heteroatoms independently selected from S, and O,
optionally substituted with one to three independently selected
R.sup.5 groups, 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, optionally
substituted with one to three independently selected R.sup.6
groups, or C.sub.6-10 aryl optionally substituted with one or more
independently selected R.sup.6 groups; L.sub.3 is --NR.sup.4b--;
R.sup.3 is C.sub.1-4 alkyl substituted with C.sub.6-10 aryl
optionally substituted with one or more independently selected
R.sup.7 groups, or 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, optionally
substituted with one or more independently selected R.sup.7 groups,
5-10 membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O, optionally substituted
with one or more independently selected R.sup.7 groups, or
C.sub.6-10 aryl optionally substituted with one or more
independently selected R.sup.7 groups; Each R.sup.4a and R.sup.4b
is independently selected from H, C.sub.1-4 alkyl, and C.sub.3-7
cycloalkyl; R.sup.5 is oxo or R.sup.6; R.sup.6 is OH, halo,
--NO.sub.2, C.sub.1-6 alkyl optionally substituted with one to
three groups independently selected from halo, and OH, C.sub.1-6
alkoxy optionally substituted with one to three groups
independently selected from halo, and OH, C.sub.3-7 cycloalkyl,
--C(.dbd.O)OR.sup.8, --C(.dbd.O)NR.sup.9R.sup.10,
--NHC(.dbd.O)--C.sub.1-4 alkyl, --CN, phenyl, --O-phenyl, 4-7
membered heterocycloalkyl comprising one to three heteroatoms
independently selected from N, O, and S, or 5-6 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
O, and S; optionally substituted with one or more independently
selected C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, halo, and
--C(.dbd.O)OR.sup.11; R.sup.7 is C.sub.1-4 alkyl, or halo, and each
of R.sup.8, R.sup.9, R.sup.10 and R.sup.11 is independently
selected from H and C.sub.1-4 alkyl; or pharmaceutically acceptable
salt thereof, or a pharmaceutically acceptable solvate, or the salt
of a pharmaceutically acceptable solvate thereof.
3. The method according to claim 2, wherein the compound is
according to Formula I.Ia, I.Ib, I.Ic, or I.Id: ##STR00026##
4. The method according to claim 1, wherein the compound is
according to Formula II: ##STR00027## wherein Cy is ##STR00028##
wherein X is O or S; Y is --CH.sub.2--, or S; Z is --CH.sub.2--;
each of the subscript n, m, or p is independently selected from 0,
and 1; and A is phenyl, or 5-6-membered heteroaryl comprising one
or two N-atoms; optionally substituted with one or more
independently selected R.sup.5 groups; any one of Cy1 and Cy2 is
optionally substituted by one or more independently selected
C.sub.1-4 alkyl groups; R.sup.3 is H, Me, or halo; L.sub.1 is
absent or is --O--, --S--, or --NR.sup.4a--; G is R.sup.2,
W-L.sub.2-R.sup.2, or --W-L.sub.3-R.sup.3; W is C.sub.1-4 alkylene,
C.sub.2-4 alkenylene having one double bond, or C.sub.2-4
alkynylene having one triple bond; L.sub.2 is absent or is --O--;
R.sup.2 is H, C.sub.3-8 alkyl optionally substituted with one to
three groups independently selected from OH, halo, CN, C.sub.1-6
alkoxy, C.sub.3-7 cycloalkyl, 4-6 membered heterocycloalkyl
(comprising one to three heteroatoms independently selected from S,
and O), 5-6 membered heteroaryl (comprising one to three
heteroatoms independently selected from N, S, and O), and phenyl,
C.sub.4-7 cycloalkenyl comprising one double bond, 5-7 membered
heterocycloalkenyl comprising one double bond, and one to three
heteroatoms independently selected from O, and S, C.sub.3-7
cycloalkyl (optionally substituted with one or more independently
selected R.sup.6 groups), 4-10 membered heterocycloalkyl comprising
one to two heteroatoms independently selected from S, and O,
(optionally substituted with one to three independently selected
R.sup.6 groups), 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O (optionally
substituted with one to three independently selected R.sup.7
groups), or C.sub.6-10 aryl (optionally substituted with one or
more independently selected R.sup.7 groups); L.sub.3 is
--NR.sup.4b; R.sup.3 is C.sub.1-4 alkyl substituted with C.sub.6-10
aryl (optionally substituted with one or more independently
selected R.sup.8 groups), or 5-10 membered heteroaryl comprising
one to three heteroatoms independently selected from N, S, and O,
(optionally substituted with one or more independently selected
R.sup.8 groups), 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, (optionally
substituted with one or more independently selected R.sup.8
groups), or C.sub.6-10 aryl (optionally substituted with one or
more independently selected R.sup.8 groups); each R.sup.4a and
R.sup.4b is independently selected from H, C.sub.1-4 alkyl, and
C.sub.3-7 cycloalkyl; R.sup.5 is halo, C.sub.1-4 alkyl or C.sub.1-4
alkoxy; R.sup.6 is oxo or R.sup.7; R.sup.7 is OH, halo, --NO.sub.2,
C.sub.1-6 alkyl (optionally substituted with one to three groups
independently selected from halo, and OH), C.sub.1-6 alkoxy
(optionally substituted with one to three groups independently
selected from halo, and OH), C.sub.3-7 cycloalkyl,
--C(.dbd.O)OR.sup.9, --C(.dbd.O)NR.sup.10R.sup.11,
--NHC(.dbd.O)--C.sub.1-4 alkyl, --CN, phenyl, --O-phenyl, 4-7
membered heterocycloalkyl comprising one to three heteroatoms
independently selected from N, O, and S, or 5-6 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
O, and S; (optionally substituted with one or more independently
selected C.sub.1-4 alkyl, C.sub.1-4 alkoxy, CN, halo, and
--C(.dbd.O)OR.sup.12); R.sup.8 is C.sub.1-4 alkyl, or halo; and
each of R.sup.9, R.sup.10, R.sup.11 and R.sup.12, is independently
selected from H and C.sub.1-4 alkyl; or pharmaceutically acceptable
salt thereof, or a pharmaceutically acceptable solvate, or the salt
of a pharmaceutically acceptable solvate thereof.
5. The method according to claim 1, wherein the compound is
according to Formula III: ##STR00029## wherein R.sup.1 is H,
C.sub.1-4 alkyl, or cyclopropyl; L.sub.A is O or NH; G.sub.A is:
4-6 membered monocyclic heterocycloalkyl containing one or two O,
C.sub.3-7 monocyclic cycloalkyl, or a bicyclic group of formula Cy:
##STR00030## wherein A is phenyl or 5-6 membered heteroaryl
containing one or two heteroatoms independently selected from N, O
and S; each R.sup.2a and R.sup.2b are independently H or
--CH.sub.3; R.sup.3 is H, --OH or --OCH.sub.3; R.sup.4 is --CN or
-L.sub.1-W.sub.1-G.sub.1, wherein L.sub.1 is absent or O, W.sub.1
is absent, or is C.sub.1-6 alkylene, C.sub.2-4 alkenylene having
one double bond or C.sub.2-4 alkynylene having one triple bond,
each of which is optionally substituted with one or more
independently selected halo, CN or C.sub.1-4 alkoxy, G.sub.1 is H,
--CF.sub.3, --C(O)--C.sub.1-4 alkyl, --S(.dbd.O).sub.2--C.sub.1-4
alkyl, optionally substituted with one or more independently
selected halo, 4-6 membered monocyclic heterocycloalkyl containing
one or two O (which heterocycloalkyl is optionally substituted with
one or more independently selected R.sup.7 groups), 6 membered
monocyclic heterocycloalkenyl containing one or two O (which
heterocycloalkenyl is optionally substituted with one or more
independently selected R.sup.7 groups), C.sub.3-7 monocyclic
cycloalkyl optionally substituted with one or more independently
selected R.sup.7 groups, phenyl optionally substituted with one or
more independently selected R.sup.7 groups, or 5-6 membered
heteroaryl containing one to four heteroatoms independently
selected from N, O and S (which heteroaryl is optionally
substituted with one or more independently selected R.sup.7
groups), each R.sup.7 is: halo, --OH, C.sub.1-4 alkyl, C.sub.3-4
monocyclic cycloalkyl, or C.sub.1-4 alkoxy, each of which is
optionally substituted with one or more independently selected
halo; R.sup.5 is --CN or -L.sub.2-W.sub.2-G.sub.2, wherein L.sub.2
is absent, O or S, W.sub.2 is absent or C.sub.1-4 alkylene,
optionally substituted with one or more independently selected
halo, G.sub.2 is H, --CF.sub.3, C.sub.3-7 monocyclic cycloalkyl
(which cycloalkyl is optionally substituted with one or more
independently selected halo), phenyl, or 5-6 membered heteroaryl
containing one to three heteroatoms independently selected from N,
O and S; and R.sup.6 is H, --OH or --OCH.sub.3; or pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate,
or the salt of a pharmaceutically acceptable solvate thereof.
6. The method according to claim 1, wherein the compound is
according to Formula IV: ##STR00031## wherein L.sub.A is O, or NH;
Cy.sub.A is monocyclic 4-6 membered heterocycloalkyl, comprising
one or two O atoms; each R.sup.A is independently selected from
halo, and C.sub.1-3 alkyl; the subscript n is 0, 1 or 2; R.sup.1 is
H or C.sub.1-3 alkyl; R.sup.2 is H, --OH, or C.sub.1-3 alkoxy;
R.sup.3 is H or C.sub.1-3 alkoxy; R.sup.4 is --CN, --OH,
--O--S(.dbd.O).sub.2--C.sub.1-4 alkyl optionally substituted with
one or more independently selected halo, or
-L.sub.1_W.sub.1-G.sub.1; L.sub.1 is a direct bond, --O--, --S--,
--SO.sub.2--, --C(.dbd.O)NR.sup.5a--, --NR.sup.5bC(.dbd.O)--, or
NR.sup.5c--; R.sup.5a, R.sup.5b and R.sup.5c are independently H or
C.sub.1-4 alkyl; W.sub.1 is a direct bond or C.sub.1-2 alkylene
optionally substituted with one or more independently selected
halo; G.sub.1 is C.sub.3-6 cycloalkyl optionally substituted with
one or more independently selected halo, 5-6 membered heteroaryl
comprising one to four heteroatoms independently selected from N,
O, and S, which heteroaryl is optionally substituted with one or
more independently selected C.sub.1-4 alkyl, 5-7 membered
heterocycloalkenyl comprising one double bond, and one to three
heteroatoms independently selected from N, O, and S, which
heterocycloalkenyl is optionally substituted with one or more
independently selected R.sup.6, monocyclic or spiro bicyclic 4-8
membered heterocycloalkyl comprising one to three heteroatoms
independently selected from N, O, and S, which heterocycloalkyl is
optionally substituted with one or more independently selected
R.sup.6, monocyclic 4-6 membered heterocycloalkyl comprising one to
three heteroatoms independently selected from N, O, and S, fused to
one or two phenyls, C.sub.1-4 alkyl optionally substituted with one
or more independently selected halo, --NR.sup.7aR.sup.7b, or
C.sub.1-4 alkoxy, which alkoxy is optionally substituted with one
or more independently selected halo, phenyl optionally substituted
with one or more independently selected halo or C.sub.1-4 alkoxy,
which alkoxy is optionally substituted with one or more
independently selected halo; R.sup.6 is halo, .dbd.O, --CN, --OH,
--C(.dbd.O)--C.sub.1-4 alkoxy optionally substituted with one or
more independently selected halo, --C(.dbd.O)--C.sub.3-4
cycloalkyl, --S(.dbd.O).sub.2--C.sub.1-4 alkyl, C.sub.1-4 alkyl
optionally substituted by one or more independently selected
C.sub.1-3 alkoxy, halo, or --OH, C.sub.1-4 alkoxy, phenyl
optionally substituted by one or more independently selected halo,
--C(.dbd.O)-monocyclic 4-6 membered heterocycloalkyl comprising one
to three heteroatoms independently selected from N, O, and S,
--C(.dbd.O)NR.sup.8aR.sup.8b, or 5-7 membered heteroaryl comprising
one to four heteroatoms independently selected from N, O, and S,
which heteroaryl is optionally substituted with one or more
independently selected C.sub.1-4 alkyl; R.sup.7a and R.sup.7b are
independently H or C.sub.1-4 alkyl, and R.sup.8a and R.sup.8b are
independently H or C.sub.1-3 alkyl; or pharmaceutically acceptable
salt thereof, or a pharmaceutically acceptable solvate, or the salt
of a pharmaceutically acceptable solvate thereof.
7. The method according to claim 6, wherein the compound is
according to Formula IV.Ia: ##STR00032##
8. The method according to claim 1, wherein the compound is:
9-Allyloxy-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquin-
olin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-3-yl-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-4-yl-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
2-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-benzonitrile,
3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-benzonitrile,
4-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-benzonitrile,
[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquino-
lin-9-yloxy]-acetonitrile,
2-([1,4]Dioxan-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[-
6,1-a]isoquinolin-4-one,
9-(3,5-Dichloro-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[-
6,1-a]isoquinolin-4-one,
9-Benzofuran-2-yl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]-
isoquinolin-4-one,
2-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-indole-1-carboxylic acid tert-butyl ester,
2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-indol-2-yl)-6,7-dihydro-pyrimido[6,1-a]-
isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-trifluoromethyl-pyridin-3-yl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-3H-imidazol-4-ylethynyl)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one,
9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-pyridine-2-carboxylic acid methylamide,
2-([1,4]Dioxan-2-ylmethoxy)-9-pent-1-ynyl-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-pyridin-2-yl-ethyl)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-pyrazin-2-yl-ethyl)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-indol-5-yl)-6,7-dihydro-pyrimido[6,1-a]-
isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-indazol-5-yl)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one,
3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-benzamide,
5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-2-fluoro-benzamide,
N-{3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]iso-
quinolin-9-yl]-phenyl}-acetamide,
9-Cyclopropylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(1-hydroxy-cyclopentylethynyl)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-pyrimidin-5-yl-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one,
9-Cyclohex-1-enyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]-
isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(1-methyl-1H-indol-5-yl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-methyl-pyridin-3-yl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-2-ylethynyl-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-prop-1-ynyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-pent-4-ynenitrile,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-1-ynyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-phenylethynyl)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-3-ylethynyl-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one,
4-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-N-methyl-benzamide,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one,
9-(2-Chloro-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-but-1-ynyl)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one,
9-(1,5-Dimethyl-1H-pyrazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(1-methyl-1H-pyrazol-3-ylmethoxy)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-[1,2,4]oxadiazol-5-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(4-morpholin-4-yl-phenyl)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-4-fluoro-benzamide,
3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-5-fluoro-benzamide,
9-(3,3-Dimethyl-but-1-ynyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-4-ylethynyl-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-isoxazol-5-ylmethoxy)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(3,6-Dihydro-2H-pyran-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one,
5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-pyridine-2-carbonitrile,
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-isopropoxy-pyridin-3-yl)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-morpholin-4-yl-pyridin-3-yl)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one,
9-(2,3-Dimethoxy-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one,
9-(3-Chloro-2-methoxy-pyridin-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-methyl-pyridin-4-yl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-isonicotinonitrile,
9-(2,5-Dimethoxy-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5'--
yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-(2,6-Dimethoxy-pyridin-3-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-py-
rimido[6,1-a]isoquinolin-4-one,
4-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-nicotinonitrile,
9-tert-Butoxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-pyrrolidin-1-yl-pyridin-3-yl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-pyrrolidin-1-yl-pyridin-3-yl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-phenyl-oxazol-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
9-(5-tert-Butyl-oxazol-2-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one,
9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-ethyl-[1,2,4]oxadiazol-3-ylmethoxy)-6,7--
dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-methyl-[1,2,4]oxadiazol-3-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-isopropyl-[1,2,4]oxadiazol-3-ylmethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopentylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one,
9-Cyclohexylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-but-1-ynyl)-6,7-dihydro-pyrimido[-
6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-hex-1-ynyl-6,7-dihydro-pyrimido[6,1-a]isoqu-
inolin-4-one,
9-[3-(Benzyl-methyl-amino)-prop-1-ynyl]-2-([1,4]dioxan-2-ylmethoxy)-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-5-methyl-hex-1-ynyl)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-but-1-ynyl)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one,
9-Cyclopropyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pent-1-ynyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pent-1-ynyl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pent-1-ynyl)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-phenyl-but-1-ynyl)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one,
9-(3-Benzylamino-prop-1-ynyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-[(furan-2-ylmethyl)-amino]-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(1-ethyl-1H-pyrazol-4-yl)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-[1-(3-methyl-butyl)-1H-pyrazol-4-yl]-6,7-di-
hydro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-methyl-furan-2-yl)-6,7-dihydro-pyrimido[-
6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-hex-1-ynyl)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one,
9-(3,5-Dimethyl-1H-pyrazol-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
2-[2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]-
isoquinolin-9-yl]-benzonitrile,
2-[2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]-
isoquinolin-9-yl]-benzonitrile,
9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-((R)-1-[1,4]dioxan-2-ylm-
ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-ethynyl-6,7-dihydro-pyrimido[6,1-a]isoquino-
lin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-pyrimidin-2-ylethynyl-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-phenylamino-prop-1-ynyl)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-prop-1-ynyl)-6,7--
dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopentyloxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pent-1-ynyl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-but-1-ynyl)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-imidazol-1-yl-prop-1-ynyl)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
9-(2-Cyclopropyl-ethyl)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one,
9-Cyclopentyloxymethyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-propyl)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one,
9-Allyloxy-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one,
9-Allyloxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one,
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-yloxymethyl)-6,7--
dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-{3-[(pyridin-3-ylmethyl)-amino]-prop-1-ynyl-
}-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-pentyl-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
9-(2-Cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(oxetan-3-yloxymethyl)-6,7-dihydro-py-
rimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-oxetan-3-ylmethoxymethyl)-6-
,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(2,2-Dimethyl-butylamino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pentyl)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-ethyl-hexylamino)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-ethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-ethoxy-ethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-Cyclopropylmethoxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-fluoro-ethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[3-(2-methoxy-ethoxy)-prop-1-ynyl]-6,-
7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[3-(2-ethoxy-ethoxy)-prop-1-ynyl]-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[3-(2-fluoro-ethoxy)-prop-1-ynyl]-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, 9-(2,2-Dimethyl-prop
oxymethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one,
9-Cyclohexyloxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-Cyclopropylmethoxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-2-ylmethoxy)-6,7-di-
hydro-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-butyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-(4,4-Dimethyl-pentyloxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pentyl)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one,
9-(3-Cyclopropyl-propoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
9-Cyclohexylamino-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[-
6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4,4-dimethyl-pentyl)-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopentylmethoxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-butyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-phenylamino-propyl)-6,7-dihydro-py-
rimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-pentyl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-butyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-(Cyclohexyl-methyl-amino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one,
9-(Cyclohexylmethyl-amino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[(tetrahydro-pyran-4-ylmethyl)-amino]-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pentyl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-butyl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pentyl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, 9-(2,2-Dimethyl-prop
oxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquin-
olin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxy)-6,7-di-
hydro-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-4-methyl-pentyl)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxymethyl)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-([1,4]Dioxan-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquino-
lin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(oxetan-3-ylmethoxy)-6,7-di-
hydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(3-Cyclopropyl-propoxy)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-tetrahydro-pyran-4-ylethyn-
yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one.
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one,
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one, or
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-butyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one.
9. The method according to claim 1, wherein said compound is:
9-Methoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
2-(Chroman-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin--
4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-methoxy-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one,
9-Allyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]is-
oquinolin-4-one,
2-(2,3-Dihydro-benzofuran-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one,
9-Hydroxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
9-Benzyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one,
9-(Pyridin-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]iso-
quinolin-9-yloxy]-acetonitrile,
9-Butoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one,
9-Cyclopropylmethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-Phenethyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one,
9-(Pyridin-4-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
9-(Pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
9-(Pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, 9-(2-Phen
oxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one,
9-Methoxy-2-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
9-Methoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
9-Methoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile,
9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile,
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile,
9-(4-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(3-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(2-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(4-Fluoro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(2-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester,
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester,
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7--
dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetic acid tert-butyl ester,
2,9-Bis-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one,
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetic acid,
9-(3-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
9-(3-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
9-(4-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
9-(3-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(4-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-(4-Methoxy-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
9-(Naphthalen-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
9-(Naphthalen-1-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
9-(2-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
9-[2-(2-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one,
9-[2-(3-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one,
9-[2-(4-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one,
9-[2-(2-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one,
9-[2-(3-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one,
9-[2-(4-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-acetamide,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N,N-dimethyl-acetamide,
9-(2,2-Dimethoxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-2-methyl-propionamide,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1,1-dimethyl-2-morpholin--
4-yl-2-oxo-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(2-Benzyloxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
2,9-Bis-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquin-
olin-4-one,
9-(6-Phenyl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridin-2-ylmethoxy]-2-(tetrahydro-furan--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(6-Furan-3-yl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(6-Pyrimidin-5-yl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(1-Cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxy]-acetamide,
N,N-Diethyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-acetamide,
N,N-Dimethyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyr-
imido[6,1-a]isoquinolin-9-yloxy]-acetamide,
N-Isopropyl-N-methyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydr-
o-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetamide,
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxy]-N-phenyl-acetamide,
9-(1-Propyl-1H-tetrazol-5-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(Oxazol-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N,N-diethyl-acetamide,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N-isopropyl-N-methyl-acetamide,
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N-phenyl-acetamide,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1-propyl-1H-tetrazol-5-yl-
methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(1-Butyl-1H-tetrazol-5-ylmethoxy)-2-(2,3-dihydro-benzo[1,4]dioxin-2-ylm-
ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-ethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetonitrile,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-oxo-2-pyrrolidin-1-yl-e-
thoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(1-Cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-(2,3-dihydro-benzo[1,4]dioxin-
-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1H-tetrazol-5-ylmethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Allyloxy-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one,
N-Benzyl-2-[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydr-
o-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetamide,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-pyrrolidin-1-yl-ethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-piperidin-1-yl-ethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(3-piperidin-1-yl-propoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(3-dimethylamino-propoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-[2-(1-methyl-pyrrolidin-2--
yl)-ethoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-[3-(4-methyl-piperazin-1-y-
l)-propoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
5-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxymethyl]-furan-2-carboxylic acid ethyl
ester,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(5-Phenyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile,
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile,
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-morpholin-4-y-
l-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(pyridin-2-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[2-(1-methyl-pyr-
rolidin-2-yl)-ethoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-tetrazol-5-y-
lmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Pyridin-3-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one,
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile,
9-Phenyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-4-yl-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile,
9-(2-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-(3-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-(4-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile,
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzoic acid,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzoic acid,
9-(4-Dimethylamino-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzamide,
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile,
9-(1-Methyl-1H-pyrazol-4-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one,
N,N-Dimethyl-3-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyr-
imido[6,1-a]isoquinolin-9-yl]-benzamide,
9-(6-Methoxy-pyridin-3-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
9-(2,6-Dimethyl-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one,
9-(3,5-Dimethyl-isoxazol-4-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one,
9-Naphthalen-2-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one,
9-Naphthalen-1-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one,
9-Pyrimidin-5-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one,
9-(5-Chloro-thiophen-2-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one,
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-pyrrole-1-carboxylic acid tert-butyl ester,
Trifluoro-methanesulfonic acid
4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]isoq-
uinolin-9-yl ester,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one,
9-(3,3-Dimethyl-but-1-ynyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(pyridin-4-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-3-yl-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pheny-
l)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-indazol-5-yl-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyrimidin-5-yl-6-
,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzamide,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-dimethylamino-
-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-3-ylethy-
nyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methoxy-prop--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(4-hydroxy-but-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1,5-dimethyl-1H-
-pyrazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-[1,2,4-
]oxadiazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-met-
hyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-4-ylethy-
nyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-prop--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-methyl-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethox-
y)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethox-
y)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1-hydroxy-cyclo-
pentylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pent-4-ynenitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3,3-dimethyl-bu-
t-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one,
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carb oxylic acid
methylamide,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-furan-3-yl-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1-methyl-1H-pyr-
azol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-morpholin-4-ylme-
thyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-ylamino]-acetonitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carbonitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[(oxazol-2-ylmet-
hyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-methyl-[1,2,4-
]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-ethyl-[1,2,4]-
oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(2,3-dihydro-[1,4]dioxin-
o[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-isopropyl-[1,-
2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(2,3-dihydro-[1,4]dioxino-
[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-isoxaz-
ol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(3-Chloro-2-methoxy-pyridin-4-yl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyr-
idin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3,6-dihydro-2H--
pyran-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carbonitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-ethoxy-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-ethoxy-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-morpholin-4-y-
l-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pyrim-
idin-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2,3-dimethoxy-p-
henyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2,5-dimethoxy-p-
henyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-phe-
nyl-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
3-{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-di-
hydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyloxy}-propionitrile,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methylamino-p-
rop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-dimethylamino-
-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-[3-(Benzyl-methyl-amino)-prop-1-ynyl]-2-(2,3-diohydro-[1,4]dioxino[2,3--
b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[3-(1,1-dioxo-th-
iomorpholin-4-yl)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-on-
e,
{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-di-
hydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyl}-urea,
1-{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-di-
hydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyl}-imidazolidine-2,4-d-
ione,
9-(3-Diethylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyr-
idin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(3-Amino-3-methyl-but-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-
-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(tetrahydro-pyra-
n-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-pyrazol-4-yl-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-but-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-pent--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-hex-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(1-Amino-cyclohexylethynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-5-met-
hyl-hex-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-ethyl-3-hydro-
xy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-phe-
nyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-4-met-
hyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-[(R)-1-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)
methoxy]-9-(oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4--
one, 2-[(R)-1-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)
methoxy]-9-(oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4--
one,
2-[(S)-1-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9-(oxa-
zol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(3-Butylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2--
ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-morpholin-4-y-
l-ethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(3-Benzylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-phenylamino-p-
rop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carb oxylic acid
(tetrahydro-pyran-4-yl)-amide,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carboxylic acid
(oxetan-3-ylmethyl)-amide,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyrrolidin-1-ylm-
ethyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-(tert-Butylamino-methyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl-
methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-piperidin-1-ylme-
thyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-oxetan-
-3-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-oxetan-
-3-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxetan-3-yloxym-
ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-(4-isopropyl-oxetan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, or
9-Cyclopropylethynyl-2-((R)-4-isopropyl-oxetan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one.
10. The method according to claim 1, wherein said compound is:
9-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-10-(2,2,2-trif-
luoro-ethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methy-
l-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-(2,2-difluoro-cyclopropylmethoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10--
methoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
10-(2,2-difluoro-ethoxy)-2-[([1,4]dioxan-2-ylmethyl)-amino]-9-methoxy-1-m-
ethyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-(2,2-difluoro-ethoxy)-10-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmeth-
yl)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
10-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-9-(2,2,2-trif-
luoro-ethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-(6-cyclopropyl-pyridin-3-yl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-metho-
xy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-(2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-9,10-dimethoxy-6,7-d-
ihydro-pyrido[2,1-a]isoquinolin-4-one, trifluoro-methanesulfonic
acid
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-4-oxo-6,7-dihydro-4-
H-pyrido[2,1-a]isoquinolin-9-yl ester,
2-[([1,4]dioxan-2-ylmethyl)-amino]-9-methoxy-1-methyl-10-(2,2,2-trifluoro-
-ethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
10-(2,2-difluoro-ethoxy)-9-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmeth-
yl)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-9-[6-(2,2,2-trifluo-
ro-ethoxy)-pyridin-3-yl]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(6-fluoro-pyridin-3-yl)-10-methoxy-1--
methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9,10-bis-(2,2-difluoro-cyclopropylmethoxy)-2-((S)-1-[1,4]dioxan-2-ylmetho-
xy)-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-(3,3-difluoro-cyclobutylmethoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-m-
ethoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-9-(2,2,2-trifluoro--
ethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
10-difluoromethoxy-9-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-am-
ino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
10-(2,2-difluoro-ethoxy)-9-methoxy-1-methyl-2-(tetrahydro-pyran-2-ylmethy-
l)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-9-(6-oxo-1,6-dihydr-
o-pyridin-3-yl)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-9-(3-methyl-oxetan--
3-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-methoxy-1-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-10-(2,2,2-trif-
luoro-ethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-(2,2-difluoro-ethoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-me-
thyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-[([1,4]dioxan-2-ylmethyl)-amino]-9,10-dimethoxy-1-methyl-6,7-dihydro-py-
rido[2,1-a]isoquinolin-4-one,
9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-dihyd-
ro-pyrido[2,1-a]isoquinolin-4-one,
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-hydroxy-10-methoxy-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one,
9-difluoromethoxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-6-
,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-cyclopropylmethoxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methy-
l-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(4-ethoxy-3-trifluoromethyl-phenyl)-1-
0-methoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9,10-dimethoxy-1-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihyd-
ro-pyrido[2,1-a]isoquinolin-4-one,
8,9-dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[-
2,1-a]isoquinolin-4-one,
9,10-dimethoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihyd-
ro-pyrido[2,1-a]isoquinolin-4-one,
10-difluoromethylsulfanyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-methoxy-1-m-
ethyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-py-
rido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-9-(4-trifluorometho-
xy-phenyl)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-(2,2-difluoro-cyclopropylmethoxy)-1-methyl-2-[(tetrahydro-furan-2-ylmet-
hyl)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
8,9-dimethoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one,
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9,10-dimethoxy-1-methyl-6,7--
dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-methoxy-1,10-dimethyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one,
8,11-dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one,
2-[([1,4]dioxan-2-ylmethyl)-amino]-8,11-dimethoxy-6,7-dihydro-pyrido[2,1--
a]isoquinolin-4-one,
8,11-dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one,
2-[(R)-1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9,10-dimet-
hoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-[([1,4]dioxan-2-ylmethyl)-amino]-8,9-dimethoxy-1-methyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one,
10-(2,2-difluoro-ethoxy)-9-methoxy-1-methyl-2-(tetrahydro-pyran-2-ylmetho-
xy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
8,9-dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[-
2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-8,9-dimethoxy-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one,
2-[(S)-1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9,10-dimet-
hoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(pyridin-2-ylmethoxy)-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one,
2-[([1,4]dioxan-2-ylmethyl)-amino]-8,9-dimethoxy-6,7-dihydro-pyrido[2,1-a-
]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-4-oxo-6,7-dihydro-4-
H-pyrido[2,1-a]isoquinoline-9-carbonitrile,
9-methoxy-1-methyl-2-(tetrahydro-pyran-2-ylmethoxy)-10-(2,2,2-trifluoro-e-
thoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-(2-cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one,
9-(2-cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-
-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-9-(pyridin-2-ylmethoxy)-
-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9,11-dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one,
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9,10-dimethoxy-6,7-dihydro-p-
yrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9,10-dimethoxy-1-methyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one, methanesulfonic acid
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-4-oxo-6,7-dihydro-4-
H-pyrido[2,1-a]isoquinolin-9-yl ester,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-9-pentyl-6,7-dihydro-py-
rido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(3-methyl-butyl)-6,7-dihydro-
-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-6,7-dihydro-pyrido[-
2,1-a]isoquinolin-4-one,
2-([1,4]dioxan-2-ylmethoxy)-9,10-dimethoxy-6,7-dihydro-pyrido[2,1-a]isoqu-
inolin-4-one,
8,11-dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(5-ethyl-[1,2,4]oxadiazol-3-ylmethoxy-
)-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-[([1,4]dioxan-2-ylmethyl)-amino]-9,11-dimethoxy-6,7-dihydro-pyrido[2,1--
a]isoquinolin-4-one,
8,9-dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]i-
soquinolin-4-one,
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one,
9-methoxy-1-methyl-10-(pyridin-2-ylmethoxy)-2-[(tetrahydro-furan-2-ylmeth-
yl)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-(3,5-dimethyl-isoxazol-4-yl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-
-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-benzyloxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one,
9,11-dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-hydroxy-10-methoxy-1-methyl-6,7-dihyd-
ro-pyrido[2,1-a]isoquinolin-4-one,
8,9-dimethoxy-1-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one,
9-benzyloxy-1-cyclopropyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-8,11-dimethoxy-6,7-dihydro-pyrido[2,1-a-
]isoquinolin-4-one,
9-(3,6-dihydro-2H-pyran-4-yl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl--
6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-9-(oxazol-2-ylmethoxy)--
6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9,11-dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(tetrahydro-pyran-4-yl)-6,7--
dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-benzyloxy-2-([1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-6,7-dihydro-pyrid-
o[2,1-a]isoquinolin-4-one,
[2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-4-oxo-6,7-dihydro-4H-pyrido[2-
,1-a]isoquinolin-9-yloxy]-acetonitrile,
9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-6,-
7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9,10-dimethoxy-1-methyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
do[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(3-methyl-but-1-ynyl)-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one,
9-(5,6-dihydro-[1,4]dioxin-2-yl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-meth-
yl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-ethoxy-1-methyl-6,7-dihydro-pyrido[2,-
1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(1-methyl-1H-pyrazol-4-yl)-6-
,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
[2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-4-oxo-6,7-dihydro-4H-pyrido[2,-
1-a]isoquinolin-9-yloxy]-acetonitrile,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(1-propyl-1H-tetrazol-5-ylme-
thoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-8,9-dimethoxy-1-methyl-6,7-dihydro-pyri-
do[2,1-a]isoquinolin-4-one,
8,11-dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one,
9-[1,4]dioxan-2-yl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-dihydro-
-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-methoxy-1-methyl-6,7-dihydro-pyrido[2-
,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-8-hydroxy-9-methoxy-1-methyl-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one,
9-(1-cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-((S)-1-[1,4]dioxan-2-ylmethox-
y)-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-4-oxo-9-(2,2,2-trifluoro-ethox-
y)-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-10-carbonitrile,
2,9-bis-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-dihydro-pyrido[2,1-a-
]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9,11-dimethoxy-6,7-dihydro-pyrido[2,1-a-
]isoquinolin-4-one,
8,9-dimethoxy-1-methyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrid-
o[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(3-methyl-oxetan-3-ylmethoxy-
)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one,
9,10-dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(pyridin-2-ylmethoxy)-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(1H-tetrazol-5ylmethoxy)-6,7--
dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-cyclohexylmethoxy-9,10-dimethoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoq-
uinolin-4-one,
9,10-dimethoxy-1-methyl-2-[(tetrahydro-pyran-3-ylmethyl)-amino]-6,7-dihyd-
ro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(1-methyl-1H-pyrazol-4-yl)-6,-
7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9,10-dimethoxy-1-methyl-2-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyri-
do[2,1-a]isoquinolin-4-one,
9-cyclopropylmethoxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-6,-
7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
8,9-dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]i-
soquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(3-methoxy-but-1-ynyl)-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one,
8,9-dimethoxy-1-methyl-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrid-
o[2,1-a]isoquinolin-4-one,
9-benzyloxy-1-cyclopropyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-p-
yrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(3-methyl-but-1-ynyl)-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one, trifluoro-methanesulfonic acid
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-4-oxo-6,7-dihydro-4H-pyrido[2,1-
-a]isoquinolin-9-yl ester,
9-(2-cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one,
9-cyclopropylmethoxy-2-([1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(3-methyl-butyl)-6,7-dihydro--
pyrido[2,1-a]isoquinolin-4-one,
9,11-dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-hydroxy-1,7,7-trimethyl-6,7-dihydro-p-
yrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-methoxy-1-methyl-4-oxo-6,7-dihydro-4H-
-pyrido[2,1-a]isoquinoline-10-carbonitrile,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-pentyl-6,7-dihydro-pyrido[2,1-
-a]isoquinolin-4-one,
1-cyclopropyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-pentyl-6,7-dihydro-pyri-
do[2,1-a]isoquinolin-4-one,
9-benzyloxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(3-methoxy-butyl)-6,7-dihydro-
-pyrido[2,1-a]isoquinolin-4-one,
1-cyclopropyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-methyl-butyl)-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one,
1-cyclopropyl-9-(2-cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6-
,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
trifluoro-methanesulfonic acid
1-cyclopropyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
do[2,1-a]isoquinolin-9-yl ester, trifluoro-methanesulfonic acid
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-4-oxo-6,7-dihydro-4H-pyrido-
[2,1-a]isoquinolin-9-yl ester,
1-cyclopropyl-9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7--
dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-9-(3-methyl-butyl)-6,7-dihy-
dro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-hydroxy-8-methoxy-1-methyl-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one,
9-(2-cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-6,7-
-dihydro-pyrido[2,1-a]isoquinolin-4-one,
1-cyclopropyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-methyl-but-1-ynyl)-6-
,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-([1,4]dioxan-2-ylmethoxy)-9-(2-methoxy-ethoxy)-1-methyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-9-(3-methyl-but-1-ynyl)-6,7-
-dihydro-pyrido[2,1-a]isoquinolin-4-one,
9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-hydroxy-1-methyl-6,7-dihydro-pyrido[2-
,1-a]isoquinolin-4-one, trifluoro-methanesulfonic acid
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-4-oxo-6,7-dihydro-4H-pyrido[2,-
1-a]isoquinolin-9-yl ester,
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-hydroxy-6,7-dihydro-pyrido[2,-
1-a]isoquinolin-4-one,
9-methoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,1--
a]isoquinolin-4-one,
10-hydroxy-9-methoxy-1-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-
-dihydro-pyrido[2,1-a]isoquinolin-4-one,
2-[([1,4]dioxan-2-ylmethyl)-amino]-10-hydroxy-9-methoxy-1-methyl-6,7-dihy-
dro-pyrido[2,1-a]isoquinolin-4-one,
10-hydroxy-9-methoxy-1-methyl-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one, or
10-benzyloxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-methoxy-1-methyl-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one.
11. The method according to claim 1, wherein said compound is:
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9,10-dimethoxy-1-methyl-6,7-dihydrobenz-
o[a]quinolizin-2-one,
9,10-dimethoxy-1-methyl-4-(tetrahydrofuran-2-ylmethylamino)-6,7-dihydrobe-
nzo[a]quinolizin-2-one,
1-ethyl-9-hydroxy-4-(tetrahydrofuran-2-ylmethylamino)-6,7-dihydrobenzo[a]-
quinolizin-2-one,
9,10-Dimethoxy-4-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-2-one,
4-[([1,4]Dioxan-2-ylmethyl)-amino]-9,10-dimethoxy-6,7-dihydro-pyrido[2,1--
a]isoquinolin-2-one,
4-[[(2R)-1,4-dioxan-2-yl]methylamino]-9,10-dimethoxy-1-methyl-6,7-dihydro-
benzo[a]quinolizin-2-one,
9-(2,2-Difluoro-cyclopropylmethoxy)-1-methyl-4-[(tetrahydro-furan-2-ylmet-
hyl)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-2-one,
1-methyl-4-(tetrahydrofuran-2-ylmethylamino)-9-(2,2,2-trifluoroethoxy)-6,-
7-dihydrobenzo[a]quinolizin-2-one,
-Methyl-4-[(tetrahydro-furan-2-ylmethyl)-amino]-9-(tetrahydro-furan-2-ylo-
xy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-2-one,
8,9-dimethoxy-1-methyl-4-(tetrahydrofuran-2-ylmethylamino)-6,7-dihydroben-
zo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-8,9-dimethoxy-1-methyl-6,7-dihydrobenzo-
[a]quinolizin-2-one,
9-(2,2-difluoroethoxy)-1-methyl-4-(tetrahydropyran-2-ylmethylamino)-6,7-d-
ihydrobenzo[a]quinolizin-2-one,
1-methyl-4-(tetrahydropyran-2-ylmethylamino)-9-(2,2,2-trifluoroethoxy)-6,-
7-dihydrobenzo[a]quinolizin-2-one,
8,9-dimethoxy-1-methyl-4-(tetrahydropyran-2-ylmethylamino)-6,7-dihydroben-
zo[a]quinolizin-2-one,
4-(1,4-dioxan-2-ylmethylamino)-8,9-dimethoxy-1-methyl-6,7-dihydrobenzo[a]-
quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2,2,2-trifluoroethoxy)-6,7--
dihydrobenzo[a]quinolizin-2-one,
4-(1,4-dioxan-2-ylmethylamino)-8,9-dimethoxy-6,7-dihydrobenzo[a]quinolizi-
n-2-one,
8,9-dimethoxy-4-(tetrahydrofuran-2-ylmethylamino)-6,7-dihydrobenz-
o[a]quinolizin-2-one,
4-(1,4-dioxan-2-ylmethylamino)-9-hydroxy-8-methoxy-6,7-dihydrobenzo[a]qui-
nolizin-2-one,
4-(1,4-dioxan-2-ylmethylamino)-8-hydroxy-9-methoxy-6,7-dihydrobenzo[a]qui-
nolizin-2-one,
9-(2,2-Difluoro-ethoxy)-4-[([1,4]dioxan-2-ylmethyl)-amino]-8-methoxy-1-me-
thyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-2-one,
9-(2,2-Difluoro-ethoxy)-8-methoxy-1-methyl-4-[(tetrahydro-furan-2-ylmethy-
l)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]quino-
lizine-9-carbonitrile,
9-(2,2-difluoroethoxy)-1-ethyl-4-(tetrahydrofuran-2-ylmethylamino)-6,7-di-
hydrobenzo[a]quinolizin-2-one,
1-ethyl-4-(tetrahydrofuran-2-ylmethylamino)-9-(2,2,2-trifluoroethoxy)-6,7-
-dihydrobenzo[a]quinolizin-2-one,
8,9-dimethoxy-1-methyl-4-(tetrahydrofuran-2-ylmethoxy)-6,7-dihydrobenzo[a-
]quinolizin-2-one,
8,9-dimethoxy-1-methyl-4-(tetrahydropyran-2-ylmethoxy)-6,7-dihydrobenzo[a-
]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(tetrahydropyran-4-ylmethoxy-
)-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2-pyridylmethoxy)-6,7-dihyd-
robenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[[3-(trifluoromethoxy)phenyl-
]methoxy]-6,7-dihydrobenzo[a]quinolizin-2-one,
9-benzyloxy-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrobenzo[a-
]quinolizin-2-one,
9-benzyloxy-4-[[(2R)-1,4-dioxan-2-yl]methylamino]-1-methyl-6,7-dihydroben-
zo[a]quinolizin-2-one,
9-(2,2-difluoroethoxy)-4-[[(2R)-1,4-dioxan-2-yl]methylamino]-1-methyl-6,7-
-dihydrobenzo[a]quinolizin-2-one,
4-[[(2R)-1,4-dioxan-2-yl]methylamino]-1-methyl-9-(2,2,2-trifluoroethoxy)--
6,7-dihydrobenzo[a]quinolizin-2-one,
[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]quin-
olizin-9-yl]trifluoromethanesulfonate,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[(1-methylpyrazol-4-yl)metho-
xy]-6,7-dihydrobenzo[a]quinolizin-2-one,
9-(3,6-dihydro-2H-pyran-4-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl--
6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(1-ethylpyrazol-4-yl)-1-methyl-6,7-di-
hydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-tetrahydropyran-4-yl-6,7-dih-
ydrobenzo[a]quinolizin-2-one,
1-methyl-4-[[(2S)-tetrahydrofuran-2-yl]methylamino]-9-(2,2,2-trifluoroeth-
oxy)-6,7-dihydrobenzo[a]quinolizin-2-one,
1-methyl-9-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]-4-(tetrahydrofuran-2--
ylmethoxy)-6,7-dihydrobenzo[a]quinolizin-2-one,
1-methyl-9-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]-4-(tetrahydropyran-2--
ylmethoxy)-6,7-dihydrobenzo[a]quinolizin-2-one,
1-methyl-9-(2-pyridylmethoxy)-4-(tetrahydrofuran-2-ylmethoxy)-6,7-dihydro-
benzo[a]quinolizin-2-one,
1-methyl-9-(2-pyridylmethoxy)-4-(tetrahydropyran-2-ylmethoxy)-6,7-dihydro-
benzo[a]quinolizin-2-one,
1-methyl-4-(tetrahydrofuran-2-ylmethoxy)-9-(tetrahydropyran-3-ylmethoxy)--
6,7-dihydrobenzo[a]quinolizin-2-one,
1-methyl-4-(tetrahydropyran-2-ylmethoxy)-9-(tetrahydropyran-3-ylmethoxy)--
6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(tetrahydropyran-3-ylmethoxy-
)-6,7-dihydrobenzo[a]quinolizin-2-one,
1-methyl-9-[(6-methyl-3-pyridyl)methoxy]-4-(tetrahydrofuran-2-ylmethoxy)--
6,7-dihydrobenzo[a]quinolizin-2-one,
1-methyl-9-[(6-methyl-3-pyridyl)methoxy]-4-(tetrahydropyran-2-ylmethoxy)--
6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[(6-methyl-3-pyridyl)methoxy-
]-6,7-dihydrobenzo[a]quinolizin-2-one,
9-(2-dimethylaminoethyloxy)-1-methyl-4-(tetrahydrofuran-2-ylmethoxy)-6,7--
dihydrobenzo[a]quinolizin-2-one,
9-(2-dimethylaminoethyloxy)-1-methyl-4-(tetrahydropyran-2-ylmethoxy)-6,7--
dihydrobenzo[a]quinolizin-2-one,
9-(2-dimethylaminoethyloxy)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,-
7-dihydrobenzo[a]quinolizin-2-one,
[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]quin-
olizin-9-yl]methanesulfonate,
1-methyl-9-(2-pyridylmethoxy)-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]-6,7--
dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[(3-methyl-1,2,4-oxadiazol-5-
-yl)methoxy]-6,7-dihydrobenzo[a]quinolizin-2-one,
9-(difluoromethoxy)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydr-
obenzo[a]quinolizin-2-one, tert-butyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperazine-1-carboxylate,
9-(2,2-difluoroethoxy)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dih-
ydrobenzo[a]quinolizin-2-one,
4,9-bis[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrobenzo[a]quinol-
izin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-morpholino-6,7-dihydrobenzo[-
a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-phenylsulfanyl-6,7-dihydrobe-
nzo[a]quinolizin-2-one,
9-(4,4-difluoro-1-piperidyl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6-
,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-piperazin-1-yl-6,7-dihydrobe-
nzo[a]quinolizin-2-one,
9-(benzenesulfonyl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydr-
obenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(4-methylsulfonylpiperazin-1-
-yl)-6,7-dihydrobenzo[a]quinolizin-2-one,
9-[4-(cyclopropanecarbonyl)piperazin-1-yl]-4-[[(2S)-1,4-dioxan-2-yl]metho-
xy]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one,
N-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]cyclopropanecarboxamide, tert-butyl
3-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]azetidine-1-carboxylate,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[2-(trifluoromethoxy)ethoxy]-
-6,7-dihydrobenzo[a]quinolizin-2-one,
N-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-N-methyl-cyclopropanecarboxamide, tert-butyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylate, tert-butyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-1-carboxylate, methyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylate, ethyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylate, isopropyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylate,
2,2,2-trifluoroethyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylate, methyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-1-carboxylate, ethyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-1-carboxylate, isopropyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-1-carboxylate, 2,2,2-trifluoroethyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-1-carboxylate,
N-cyclopropyl-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydr-
obenzo[a]quinolizine-9-carboxamide,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-hydroxy-1-methyl-6,7-dihydrobenzo[a]q-
uinolizin-2-one,
9-(3,3-difluoroazetidin-1-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl--
6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(6-oxa-2-azaspiro[3.3]heptan-
-2-yl)-6,7-dihydrobenzo[a]quinolizin-2-one,
N-cyclopropyl-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-N,1-dimethyl-2-oxo-6,7-di-
hydrobenzo[a]quinolizine-9-carboxamide,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-methoxy-1-methyl-6,7-dihydrobenzo[a]q-
uinolizin-2-one,
4-(1,4-dioxan-2-ylmethoxy)-1-methyl-9-(2,2,2-trifluoroethoxy)-6,7-dihydro-
benzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(3-fluoroazetidin-1-yl)-1-methyl-6,7--
dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-[3-(1-hydroxy-1-methyl-ethyl)azetidin-
-1-yl]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one,
9-(azetidin-1-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrob-
enzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(3-methylsulfonylazetidin-1--
yl)-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(3-pyrazol-1-ylazetidin-1-yl-
)-6,7-dihydrobenzo[a]quinolizin-2-one,
9-(3,3-dimethylazetidin-1-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl--
6,7-dihydrobenzo[a]quinolizin-2-one, methyl
1-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]azetidine-3-carboxylate,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(3-pyridyl)-6,7-dihydrobenzo-
[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(3-fluorophenyl)-1-methyl-6,7-dihydro-
benzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(4-pyridyl)-6,7-dihydrobenzo-
[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2-pyridyl)-6,7-dihydrobenzo-
[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(3-methyl-2-pyridyl)-6,7-dih-
ydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(4-methyl-2-pyridyl)-6,7-dih-
ydrobenzo[a]quinolizin-2-one, tert-butyl
3-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]azetidine-1-carboxylate,
3-deuterio-9-(1-deuterio-2,2-difluoro-vinyloxy)-4-[[(2S)-1,4-dioxan-2-yl]-
methoxy]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one,
9-(1,1-dideuterio-2,2,2-trifluoro-ethoxy)-4-[[(2S)-1,4-dioxan-2-yl]methox-
y]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one,
9-benzyloxy-1-methyl-4-(oxetan-2-ylmethoxy)-6,7-dihydrobenzo[a]quinolizin-
-2-one,
9-benzyloxy-1-methyl-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]-6,7-di-
hydrobenzo[a]quinolizin-2-one,
9-benzyloxy-1-methyl-4-(tetrahydropyran-2-ylmethoxy)-6,7-dihydrobenzo[a]q-
uinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(3-methoxyazetidin-1-yl)-1-methyl-6,7-
-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(4-methoxy-1-piperidyl)-1-methyl-6,7--
dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[4-(piperidine-1-carbonyl)-1-
-piperidyl]-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(4-phenyl-1-piperidyl)-6,7-d-
ihydrobenzo[a]quinolizin-2-one, methyl
1-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-4-carboxylate,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-[4-(ethoxymethyl)-1-piperidyl]-1-meth-
yl-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(1-piperidyl)-6,7-dihydroben-
zo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(3-methyl-1-piperidyl)-6,7-d-
ihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-[4-(4-fluorophenyl)-1-piperidyl]-1-me-
thyl-6,7-dihydrobenzo[a]quinolizin-2-one,
9-[1-(cyclopropanecarbonyl)azetidin-3-yl]oxy-4-[[(2S)-1,4-dioxan-2-yl]met-
hoxy]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[1-(2,2,2-trifluoroacetyl)az-
etidin-3-yl]oxy-6,7-dihydrobenzo[a]quinolizin-2-one, ethyl
3-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]azetidine-1-carboxylate,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[4-(3-pyridyloxy)-1-piperidy-
l]-6,7-dihydrobenzo[a]quinolizin-2-one,
1-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-4-carbonitrile,
9-(3,3-difluoro-1-piperidyl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6-
,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-isopropyl-1-methyl-6,7-dihydrobenzo[a-
]quinolizin-2-one,
3-deuterio-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2,2,2-trifluoroe-
thoxy)-6,7-dihydrobenzo[a]quinolizin-2-one,
3-deuterio-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(1,1,2,2-tetradeu-
terio-2-fluoro-ethoxy)-6,7-dihydrobenzo[a]quinolizin-2-one,
tert-butyl
3-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]pyrrolidine-1-carboxylate, tert-butyl
4-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]piperidine-1-carboxylate,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[methyl(3,3,3-trifluoropropy-
l)amino]-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-pyrrolidin-1-yl-6,7-dihydrob-
enzo[a]quinolizin-2-one,
9-(3,3-difluoropyrrolidin-1-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methy-
l-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[3-(trifluoromethyl)azetidin-
-1-yl]-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[4-(trifluoromethyl)-3,6-dih-
ydro-2H-pyridin-1-yl]-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[(2R)-2-methylpyrrolidin-1-y-
l]-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(3-fluoro-1-piperidyl)-1-methyl-6,7-d-
ihydrobenzo[a]quinolizin-2-one, 9-carbazol-9-yl-4-[[(2
S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one,
9-(3,5-dimethyl-1-piperidyl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6-
,7-dihydrobenzo[a]quinolizin-2-one,
9-(3,3-dimethylpyrrolidin-1-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methy-
l-6,7-dihydrobenzo[a]quinolizin-2-one,
9-(4,4-dimethyl-1-piperidyl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6-
,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[4-(trifluoromethyl)-1-piper-
idyl]-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(4-methyl-1-piperidyl)-6,7-d-
ihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2,2,2-trifluoroethylamino)--
6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2-methyl-1-piperidyl)-6,7-d-
ihydrobenzo[a]quinolizin-2-one,
9-[1-(cyclopropanecarbonyl)pyrrolidin-3-yl]oxy-4-[[(2S)-1,4-dioxan-2-yl]m-
ethoxy]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one, ethyl
3-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]pyrrolidine-1-carboxylate,
9-[1-(cyclopropanecarbonyl)azetidin-3-yl]-4-[[(2S)-1,4-dioxan-2-yl]methox-
y]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one, ethyl
3-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]azetidine-1-carboxylate,
3-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-N,N-dimethyl-azetidine-1-carboxamide,
3-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-N-isopropyl-azetidine-1-carboxamide,
3-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]-N,N-dimethyl-azetidine-1-carboxamide,
3-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-N-isopropyl-azetidine-1-carboxamide,
9-benzyloxy-4-[(4,4-dimethyloxetan-2-yl)methoxy]-1-methyl-6,7-dihydrobenz-
o[a]quinolizin-2-one,
9-benzyloxy-1-methyl-4-[(2-methyltetrahydrofuran-2-yl)methoxy]-6,7-dihydr-
obenzo[a]quinolizin-2-one,
9-benzyloxy-4-[(5,5-dimethyltetrahydrofuran-2-yl)methoxy]-1-methyl-6,7-di-
hydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2,2,3,3,3-pentafluoropropox-
y)-6,7-dihydrobenzo[a]quinolizin-2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrobenzo[a]quinolizin--
2-one,
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2-oxopyrrolidin-1-yl)-
-6,7-dihydrobenzo[a]quinolizin-2-one, or
3-deuterio-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(1,1,2,2-tetradeu-
terio-2-fluoro-ethoxy)-6,7-dihydrobenzo[a]quinolizin-2-one.
12. A method for prophylaxis and/or treatment of one or more
fibrotic diseases, comprising administering a compound or
pharmaceutically acceptable salt thereof according to claim 1, and
a pharmaceutically acceptable carrier, to a subject in need
thereof.
13. The method according to claim 12, further comprising
administering a further therapeutic agent to the subject.
14. The method according to claim 1, wherein the fibrotic disease
is NASH.
15. The method according to claim 1, wherein the fibrotic disease
is IPF.
16. The method according to claim 13, wherein the further
therapeutic agent is a fibrotic disease treatment agent.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compounds useful in the
prophylaxis and/or treatment of one or more fibrotic diseases. In
particular, it has been identified that the compounds of the
invention which antagonize GPR84, a G-protein-coupled receptor may
useful in the prophylaxis and/or treatment of one or more fibrotic
diseases. The present invention also provides pharmaceutical
compositions comprising the compounds for use and methods for the
prophylaxis and/or treatment of one or more fibrotic diseases by
administering said compound.
BACKGROUND OF THE INVENTION
[0002] Fibrosis is a process that can be triggered by chronic
tissue damage because of toxic substances, viral infection,
inflammation, or mechanical stress (Nanthakumar et al., 2015); and
may be defined as the abnormal or excessive production and
accumulation of extracellular matrix (ECM).
[0003] In particular, fibrosis is a key driver of progressive organ
dysfunction in many inflammatory and metabolic diseases, including
idiopathic pulmonary fibrosis (IPF), advanced liver disease (e.g.
non-alcoholic steatohepatitis (NASH)) and advanced kidney disease.
These conditions remain poorly treated despite advances in the
understanding of the disease mechanism and, more recently, an
increase in the number of clinical trials reflecting the need to
identify new treatments, particularly in IPF (Nanthakumar et al.,
2015).
[0004] Non-alcoholic fatty liver disease (NAFLD) is initially
characterized by pure steatosis with progression to non-alcoholic
steatohepatitis (NASH), mainly caused by excess energy intake and
physical inactivity apart from genetic defects, and closely
associated with obesity, insulin resistance, and other related
metabolic complications. (Neuschwander-Tetri and Caldwell, 2003).
If untreated, NASH leads to lethal liver failure.
[0005] The mechanisms that promote the progression from NAFLD to
NASH and end-stage liver diseases are complex and may be triggered
by an acute inflammatory insult and oxidative stress. (Day and
James, 1998).
[0006] GPR84 (also known as EX33) has been isolated and
characterized from human B cells (Wittenberger et al., 2001) and
also using a degenerate primer reverse transcriptase-polymerase
chain reaction (RT-PCR) approach (Yousefi et al., 2001). It
remained an orphan GPCR until the identification of medium-chain
Free Fatty Acids (FFAs) with carbon chain lengths of 9-14 as
ligands for this receptor (Wang et al., 2006).
[0007] GPR84 is activated by medium-chain FFAs, such as capric acid
(C10:0), undecanoic acid (C11:0) and lauric acid (12:0) which
amplify lipopolysaccharide stimulated production of
pro-inflammatory cytokines/chemokines (TNFa, IL-6, IL-8, CCL2 and
others), and is highly expressed in neutrophils and monocytes
(macrophages). (Miyamoto et al., 2016)
[0008] In contrast, GPR84-ligand mediated chemotaxis of neutrophils
and monocytes/macrophages is inhibited by GPR84 antagonists.
(Suzuki et al., 2013)
[0009] Although the recruitment of monocytes/macrophages to livers
may appear to occur concomitantly with fibrogenesis in patients
with chronic liver diseases (Marra et al., 1998; Zimmermann et al.,
2010), this has not resulted in novel therapies.
[0010] No approved drug for the treatment of NASH is available at
present, and consequently liver transplant remains the last option
for end stage disease status. In the case of IPF for example, only
two drugs have been approved despite their undesirable side effects
(Brunnemer et al., 2018; Lancaster et al., 2017; Richeldi et al.,
2014), and therefore there is clear need for improved therapies
(Raghu, 2015).
[0011] Therefore, the identification and development of novel
compounds for use in the preparation of a medicament for the
prophylaxis and/or treatment of one or more fibrotic diseases, and
more particularly NASH and/or IPF remains highly desirable.
SUMMARY OF THE INVENTION
[0012] The present invention relates to compounds useful in the
prophylaxis and/or treatment of one or more fibrotic diseases. In
particular, it has been identified that the compounds of the
invention which antagonize GPR84, a G-protein-coupled receptor may
be useful in the prophylaxis and/or treatment of one or more
fibrotic diseases. The present invention also provides
pharmaceutical compositions comprising the compounds for use and
methods for the prophylaxis and/or treatment of one or more
fibrotic diseases, by administering said compound.
[0013] Accordingly, in a first aspect of the invention, are
provided compounds having GPR84 antagonist activity for use in the
prophylaxis and/or treatment of one or more fibrotic diseases.
[0014] In a particular aspect, are provided the compounds of
Formula I, II, III, and IV, respectively disclosed in WO
2013/092791, WO 2014/095798, WO 2015/197550, and WO 2016/169911 the
entire disclosure being incorporated herein by reference for use in
the prophylaxis and/or treatment of one or more fibrotic
diseases.
[0015] The compounds of Formula I are shown below:
##STR00001##
wherein R.sup.1 is H, Me, or halo; L.sup.1 is absent or is --O--,
--S--, or --NR.sup.4a--;
G is
[0016] R.sup.2, [0017] --W-L.sub.2-R.sup.2, or [0018]
--W-L.sub.3-R.sup.3; W is C.sub.1-4 alkylene, C.sub.2-4 alkenylene
having one double bond, or C.sub.2-4 alkynylene having one triple
bond; L.sub.2 is absent or is --O--;
R.sup.2 is
[0018] [0019] H, [0020] C.sub.1-8 alkyl, optionally substituted
with one to three groups independently selected from [0021] OH,
[0022] halo, [0023] CN, [0024] C.sub.1-6 alkoxy, [0025] C.sub.3-7
cycloalkyl, [0026] 4-6 membered heterocycloalkyl comprising one to
three heteroatoms independently selected from S, and O, [0027] 5-6
membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O, and [0028] phenyl, [0029]
C.sub.4-7 cycloalkenyl comprising one double bond, [0030] 5-7
membered heterocycloalkenyl comprising one double bond, and one to
three heteroatoms independently selected from N, O, and S, [0031]
C.sub.3-7 cycloalkyl optionally substituted with one or more
independently selected R.sup.5 groups, [0032] 4-10 membered
heterocycloalkyl comprising one to two heteroatoms independently
selected from S, and O, optionally substituted with one to three
independently selected R.sup.5 groups, [0033] 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O, optionally substituted with one to three
independently selected R.sup.6 groups, or [0034] C.sub.6-10 aryl
optionally substituted with one or more independently selected
R.sup.6 groups; L.sub.3 is --NR.sup.4b--;
R.sup.3 is
[0034] [0035] C.sub.1-4 alkyl substituted with [0036] C.sub.6-10
aryl optionally substituted with one or more independently selected
R.sup.7 groups, or [0037] 5-10 membered heteroaryl comprising one
to three heteroatoms independently selected from N, S, and O,
optionally substituted with one or more independently selected
R.sup.7 groups, [0038] 5-10 membered heteroaryl comprising one to
three heteroatoms independently selected from N, S, and O,
optionally substituted with one or more independently selected
R.sup.7 groups, or [0039] C.sub.6-10 aryl optionally substituted
with one or more independently selected R.sup.7 groups; Each
R.sup.4a and R.sup.4b is independently selected from H, C.sub.1-4
alkyl, and C.sub.3-7 cycloalkyl; R.sup.5 is oxo or R.sup.6;
R.sup.6 is
[0039] [0040] OH, [0041] halo, [0042] --NO.sub.2, [0043] C.sub.1-6
alkyl optionally substituted with one to three groups independently
selected from halo, and OH, [0044] C.sub.1-6 alkoxy optionally
substituted with one to three groups independently selected from
halo, and OH, [0045] C.sub.3-7 cycloalkyl, [0046]
--C(.dbd.O)OR.sup.8, [0047] --C(.dbd.O)NR.sup.9R.sup.10, [0048]
--NHC(.dbd.O)--C.sub.1-4 alkyl, [0049] --CN, [0050] phenyl, [0051]
--O-phenyl, [0052] 4-7 membered heterocycloalkyl comprising one to
three heteroatoms independently selected from N, O, and S, or
[0053] 5-6 membered heteroaryl comprising one to three heteroatoms
independently selected from N, O, and S; optionally substituted
with one or more independently selected C.sub.1-4 alkyl, C.sub.1-4
alkoxy, CN, halo, and --C(.dbd.O)OR.sup.11; R.sup.7 is C.sub.1-4
alkyl, or halo, and each of R.sup.8, R.sup.9, R.sup.10 and R.sup.11
is independently selected from H and C.sub.1-4 alkyl.
[0054] The compounds of Formula II are shown below:
##STR00002##
wherein
Cy is
##STR00003##
[0055] wherein
X is O or S;
Y is --CH.sub.2--, or S;
Z is --CH.sub.2--;
[0056] each of the subscript n, m, or p is independently selected
from 0, and 1; and A is phenyl, or 5-6-membered heteroaryl
comprising one or two N-atoms; optionally substituted with one or
more independently selected R.sup.5 groups; any one of Cy1 and Cy2
is optionally substituted by one or more independently selected
C.sub.1-4 alkyl groups; R.sup.5 is H, Me, or halo; L.sub.1 is
absent or is --O--, --S--, or --NR.sup.4a--;
G is
[0057] R.sup.2, [0058] --W-L.sub.2-R.sup.2, or [0059]
--W-L.sub.3-R.sup.3; W is C.sub.1-4 alkylene, C.sub.2-4 alkenylene
having one double bond, or C.sub.2-4 alkynylene having one triple
bond; L.sub.2 is absent or is --O--;
R.sup.2 is
[0059] [0060] H, [0061] C.sub.1-8 alkyl optionally substituted with
one to three groups independently selected from [0062] OH, [0063]
halo, [0064] CN, [0065] C.sub.1-6 alkoxy, [0066] C.sub.3-7
cycloalkyl, [0067] 4-6 membered heterocycloalkyl (comprising one to
three heteroatoms independently selected from S, and O), [0068] 5-6
membered heteroaryl (comprising one to three heteroatoms
independently selected from N, S, and O), and [0069] phenyl, [0070]
C.sub.4-7 cycloalkenyl comprising one double bond, [0071] 5-7
membered heterocycloalkenyl comprising one double bond, and one to
three heteroatoms independently selected from O, and S, [0072]
C.sub.3-7 cycloalkyl (optionally substituted with one or more
independently selected R.sup.6 groups), [0073] 4-10 membered
heterocycloalkyl comprising one to two heteroatoms independently
selected from S, and O, (optionally substituted with one to three
independently selected R.sup.6 groups), [0074] 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O (optionally substituted with one to three
independently selected R.sup.7 groups), or [0075] C.sub.6-10 aryl
(optionally substituted with one or more independently selected
R.sup.7 groups); L.sub.3 is --NR.sup.4b--;
R.sup.3 is
[0075] [0076] C.sub.1-4 alkyl substituted with C.sub.6-10 aryl
(optionally substituted with one or more independently selected
R.sup.8 groups), or 5-10 membered heteroaryl comprising one to
three heteroatoms independently selected from N, S, and O,
(optionally substituted with one or more independently selected
R.sup.8 groups), [0077] 5-10 membered heteroaryl comprising one to
three heteroatoms independently selected from N, S, and O,
(optionally substituted with one or more independently selected
R.sup.8 groups), or [0078] C.sub.6-10 aryl (optionally substituted
with one or more independently selected R.sup.8 groups); each
R.sup.4a and R.sup.4b is independently selected from H, C.sub.1-4
alkyl, and C.sub.3-7 cycloalkyl; R.sup.5 is halo, C.sub.1-4 alkyl
or C.sub.1-4 alkoxy; R.sup.6 is oxo or R.sup.7;
R.sup.7 is
[0078] [0079] OH, [0080] halo, [0081] --NO.sub.2, [0082] C.sub.1-6
alkyl (optionally substituted with one to three groups
independently selected from halo, and OH), [0083] C.sub.1-6 alkoxy
(optionally substituted with one to three groups independently
selected from halo, and OH), [0084] C.sub.3-7 cycloalkyl, [0085]
--C(.dbd.O)OR.sup.9, [0086] --C(.dbd.O)NR.sup.10R.sup.11, [0087]
--NHC(.dbd.O)--C.sub.1-4 alkyl, [0088] --CN, [0089] phenyl, [0090]
--O-phenyl, [0091] 4-7 membered heterocycloalkyl comprising one to
three heteroatoms independently selected from N, O, and S, or
[0092] 5-6 membered heteroaryl comprising one to three heteroatoms
independently selected from N, O, and S; (optionally substituted
with one or more independently selected C.sub.1-4 alkyl, C.sub.1-4
alkoxy, CN, halo, and --C(.dbd.O)OR.sup.12); R.sup.8 is C.sub.1-4
alkyl, or halo; and each of R.sup.9, R.sup.10, R.sup.11 and
R.sup.12, is independently selected from H and C.sub.1-4 alkyl.
[0093] The compounds of Formula III are shown below:
##STR00004##
wherein R.sup.1 is H, C.sub.1-4 alkyl, or cyclopropyl;
L.sub.A is O or NH;
G.sub.A is:
[0094] 4-6 membered monocyclic heterocycloalkyl containing one or
two O, [0095] C.sub.3-7 monocyclic cycloalkyl, or [0096] a bicyclic
group of formula Cy:
##STR00005##
[0096] wherein A is phenyl or 5-6 membered heteroaryl containing
one or two heteroatoms independently selected from N, O and S; each
R.sup.2a and R.sup.2b are independently H or --CH.sub.3; R.sup.3 is
H, --OH or --OCH.sub.3; R.sup.4 is --CN or
-L.sub.1-W.sub.1-G.sub.1, wherein [0097] L.sub.1 is absent or O,
[0098] W.sub.1 is absent, or is C.sub.1-6 alkylene, C.sub.2-4
alkenylene having one double bond or C.sub.2-4 alkynylene having
one triple bond, each of which is optionally substituted with one
or more independently selected halo, --CN or C.sub.1-4 alkoxy,
[0099] G.sub.1 is [0100] H, [0101] --CF.sub.3, [0102]
--C(.dbd.O)--C.sub.1-4 alkyl, [0103] --S(.dbd.O).sub.2--C.sub.1-4
alkyl, optionally substituted with one or more independently
selected halo, [0104] 4-6 membered monocyclic heterocycloalkyl
containing one or two O (which heterocycloalkyl is optionally
substituted with one or more independently selected R.sup.7
groups), [0105] 6 membered monocyclic heterocycloalkenyl containing
one or two O (which heterocycloalkenyl is optionally substituted
with one or more independently selected R.sup.7 groups), [0106]
C.sub.3-7 monocyclic cycloalkyl optionally substituted with one or
more independently selected R.sup.7 groups, [0107] phenyl
optionally substituted with one or more independently selected
R.sup.7 groups, [0108] or 5-6 membered heteroaryl containing one to
four heteroatoms independently selected from N, O and S (which
heteroaryl is optionally substituted with one or more independently
selected R.sup.7 groups), each R.sup.7 is: [0109] halo, [0110]
--OH, [0111] C.sub.1-4 alkyl, C.sub.3-4 monocyclic cycloalkyl, or
C.sub.1-4 alkoxy, each of which is optionally substituted with one
or more independently selected halo; R.sup.5 is --CN or
-L.sub.2-W.sub.2-G.sub.2, wherein [0112] L.sub.2 is absent, O or S,
[0113] W.sub.2 is absent or C.sub.1-4 alkylene, optionally
substituted with one or more independently selected halo, [0114]
G.sub.2 is [0115] H, [0116] --CF.sub.3, [0117] C.sub.3-7 monocyclic
cycloalkyl (which cycloalkyl is optionally substituted with one or
more independently selected halo), [0118] phenyl, [0119] or 5-6
membered heteroaryl containing one to three heteroatoms
independently selected from N, O and S; and R.sup.6 is H, --OH or
--OCH.sub.3.
[0120] The compounds of Formula IV are shown below:
##STR00006##
wherein
L.sub.A is O, or NH;
[0121] Cy.sub.A is monocyclic 4-6 membered heterocycloalkyl,
comprising one or two O atoms; each R.sup.A is independently
selected from halo, and C.sub.1-3 alkyl; the subscript n is 0, 1 or
2; R.sup.1 is H or C.sub.1-3 alkyl; R.sup.2 is H, --OH, or
C.sub.1-3 alkoxy; R.sup.3 is H or C.sub.1-3 alkoxy;
R.sup.4 is
[0122] --CN, [0123] --OH, [0124] --O--S(.dbd.O).sub.2--C.sub.1-4
alkyl optionally substituted with one or more independently
selected halo, or [0125] -L.sub.1-W.sub.1-G.sub.1; L.sub.1 is a
direct bond, --O--, --S--, --C(.dbd.O)NR.sup.5a--,
--NR.sup.5bC(.dbd.O)--, or --NR.sup.5c--; R.sup.5a, R.sup.5b and
R.sup.5c are independently H or C.sub.1-4 alkyl; W.sub.1 is a
direct bond or C.sub.1-2 alkylene optionally substituted with one
or more independently selected halo;
G.sub.1 is
[0125] [0126] C.sub.3-6 cycloalkyl optionally substituted with one
or more independently selected halo, [0127] 5-6 membered heteroaryl
comprising one to four heteroatoms independently selected from N,
O, and S, which heteroaryl is optionally substituted with one or
more independently selected C.sub.1-4 alkyl, [0128] 5-7 membered
heterocycloalkenyl comprising one double bond, and one to three
heteroatoms independently selected from N, O, and S, which
heterocycloalkenyl is optionally substituted with one or more
independently selected R.sup.6, [0129] monocyclic or spiro bicyclic
4-8 membered heterocycloalkyl comprising one to three heteroatoms
independently selected from N, O, and S, which heterocycloalkyl is
optionally substituted with one or more independently selected
R.sup.6, [0130] monocyclic 4-6 membered heterocycloalkyl comprising
one to three heteroatoms independently selected from N, O, and S,
fused to one or two phenyls, [0131] C.sub.1-4 alkyl optionally
substituted with one or more independently selected halo,
--NR.sup.7aR.sup.7b, C.sub.1-4 alkoxy, which alkoxy is optionally
substituted with one or more independently selected halo, [0132]
phenyl optionally substituted with one or more independently
selected halo or C.sub.1-4 alkoxy, which alkoxy is optionally
substituted with one or more independently selected halo;
R.sup.6 is
[0132] [0133] halo, [0134] .dbd.O, [0135] --CN, [0136] --OH, [0137]
--C(.dbd.O)--C.sub.1-4 alkoxy optionally substituted with one or
more independently selected halo, [0138] --C(.dbd.O)--C.sub.3-4
cycloalkyl, [0139] --S(.dbd.O).sub.2--C.sub.1-4 alkyl, [0140]
C.sub.1-4 alkyl optionally substituted by one or more independently
selected C.sub.1-3 alkoxy, halo, or --OH, [0141] C.sub.1-4 alkoxy,
[0142] phenyl optionally substituted by one or more independently
selected halo, [0143] --C(.dbd.O)-monocyclic 4-6 membered
heterocycloalkyl comprising one to three heteroatoms independently
selected from N, O, and S, [0144] --C(.dbd.O)NR.sup.8aR.sup.8b, or
[0145] 5-7 membered heteroaryl comprising one to four heteroatoms
independently selected from N, O, and S, which heteroaryl is
optionally substituted with one or more independently selected
C.sub.1-4 alkyl; R.sup.7a and R.sup.7b are independently H or
C.sub.1-4 alkyl, and R.sup.88 and R.sup.8b are independently H or
C.sub.1-3 alkyl.
[0146] In a particular aspect, the compounds of the invention are
provided for use in the prophylaxis and/or treatment of one or more
fibrotic diseases. in a more particular aspect the fibrotic disease
is NASH.
[0147] In particular, it has now been identified that the compounds
of the invention, may induce a reduction of the NAS score in mice,
a clinical NASH diagnostic severity index, in particular the NAS
steatosis component diagnostic. In a further embodiment, the
compounds of the invention induce a reduction of the NAS score by
at least 1, at least 2, at least 3, or at least 4.
[0148] In a further embodiment, the present invention disclosed a
method for treating NASH comprising the steps of [0149] a.
Measuring the NAS score in a subject, [0150] b. Administering a
therapeutically effective amount of a compound according to Formula
I, II, III, or IV; [0151] c. Repeating step a above, [0152] d.
Calculating the response to the treatment of said subject, [0153]
e. Determining whether the dose of the compound according to
Formula I, II, III, or IV should be decreased, maintained or
increased based on the response of step d.
[0154] In a further embodiment, the present invention disclosed a
method for treating NASH comprising the steps of [0155] a.
Measuring one or more NASH associated biomarkers levels in a
subject, wherein said biomarker is selected from CCL2, Colla1,
TNF.alpha., ALT or AST. [0156] b. Administering a therapeutically
effective amount of a compound according to Formula I, II, III, or
IV; [0157] c. Repeating step a above, [0158] d. Calculating the
response to the treatment of said subject, [0159] e. Determining
whether the dose of the compound according to Formula I, II, III,
or IV should be decreased, maintained or increased based on the
response of step d.
[0160] In a further aspect, the present invention provides
pharmaceutical compositions comprising a compound of the invention,
and a pharmaceutical carrier, excipient or diluent for use in
treatment of one or more fibrotic diseases. In a particular aspect,
the pharmaceutical composition may additionally comprise further
therapeutically active ingredients suitable for use in combination
with the compounds of the invention. In a further particular
aspect, said further therapeutic agent is for the treatment and/or
prophylaxis of fibrotic disease. In a more particular aspect, the
further therapeutically active ingredient is an agent for the
treatment of NASH. Also in a more particular aspect, the further
therapeutically active ingredient is an agent for the treatment of
IPF.
[0161] Moreover, the compounds of the invention, useful in the
pharmaceutical compositions and treatment methods disclosed herein,
are pharmaceutically acceptable as prepared and used.
[0162] In a further aspect of the invention, this invention
provides a method of treating a mammal, in particular humans,
afflicted with a condition selected from among those listed herein,
and particularly NASH, which method comprises administering an
effective amount of the pharmaceutical composition or compounds of
the invention as described herein.
[0163] The present invention also provides pharmaceutical
compositions comprising a compound of the invention, and a suitable
pharmaceutical carrier, excipient or diluent for use fibrotic
diseases, and more particularly NASH.
[0164] In a further aspect of the invention, this invention
provides a method of treating a mammal, in particular humans,
suffering IPF, which method comprises administering an effective
amount of the pharmaceutical composition or compounds of the
invention as described herein.
[0165] The present invention also provides pharmaceutical
compositions comprising a compound of the invention, and a suitable
pharmaceutical carrier, excipient or diluent for use in IPF.
[0166] In additional aspects, this invention provides methods for
synthesizing the compounds of the invention, with representative
synthetic protocols and pathways disclosed later on herein.
[0167] Other objects and advantages will become apparent to those
skilled in the art from a consideration of the ensuing detailed
description.
[0168] It will be appreciated that compounds of the invention may
be metabolized to yield biologically active metabolites.
DESCRIPTION OF THE FIGURES
[0169] FIG. 1 relates to example 3.2 and shows the necrotic area
fraction [%] observed in liver samples obtained from animals in
control group 1 (C1), control group 2 (C2), test group dosed with
Compound A (CpdA) and test group dosed with Compound B (CpdB); *
means p<0.05, ** means p<0.01, *** means p<0.001.
[0170] FIG. 2 relates to example 3.2 and shows the F4/80 stained
area fraction [%] observed in liver samples obtained from animals
in control group 1 (C1), control group 2 (C2), test group dosed
with Compound A (CpdA) and test group dosed with Compound B (CpdB);
* means p<0.05, ** means p<0.01, *** means p<0.001.
[0171] FIG. 3 relates to example 3.2 and shows the percentage of
neutrophils (panel A) and of monocytes (panel B) in total leucocyte
cells of blood samples obtained from animals in control group 1
(C1), control group 2 (C2), test group dosed with Compound A (CpdA)
and test group dosed with Compound B (CpdB); ** means p<0.01, ns
means not statistically significant.
[0172] FIG. 4 relates to example 3.2 and shows the percentage of
neutrophils (panel A), of monocytes (panel B) and of MoMF in total
leucocyte cells of liver samples obtained from animals in control
group 1 (C1), control group 2 (C2), test group dosed with Compound
A (CpdA) and test group dosed with Compound B (CpdB); * means
p<0.05, ** means p<0.01, *** means p<0.001, ns means not
statistically significant.
[0173] FIG. 5 relates to example 3.3 and shows the necrotic area
fraction [%] observed in liver samples obtained from animals in
control group 1 (C1), control group 2 (C2), test group dosed with
Compound A (CpdA) and test group dosed with Compound B (CpdB); *
means p<0.05, *** means p<0.001.
[0174] FIG. 6 relates to example 3.3 and shows the F4/80 stained
area fraction [%] observed in liver samples obtained from animals
in control group 1 (C1), control group 2 (C2), test group dosed
with Compound A (CpdA) and test group dosed with Compound B (CpdB);
* means p<0.05, *** means p<0.001.
[0175] FIG. 7 relates to example 3.3 and shows
Fluorescence-activated cell sorting (FACS) results measured in
blood and liver samples obtained from animals in control group 1
(C1), control group 2 (C2), test group dosed with Compound A (CpdA)
and test group dosed with Compound B (CpdB) for CD4 cells (Panel
A), CD8 cells (Panel B), Blood monocyte (Panel C), Liver
neutrophils cells (Panel D), Liver infiltrating monocyte-derived
macrophage (MoMF) cells (Panel E), Liver CD19 cells (Panel F),
Liver Natural Killer (NK) cells (Panel G), Liver Natural Killer T
(NKT) cells (Panel H) and liver Kupfer cells (Panel I); * means
p<0.05, ** means p<0.01, *** means p<0.001, ns means not
statistically significant.
[0176] FIG. 8 relates to example 3.3 and shows gene expression of
Colla1 (panel A) and Timp1 (panel B) measured in blood samples
obtained from animals in control group 1 (C1), control group 2
(C2), test group dosed with Compound A (CpdA) and test group dosed
with Compound B (CpdB), expressed as Normalised Relative Quantity
scaled versus disease; *** means p<0.001.
[0177] FIG. 9 relates to example 3.3 and shows gene expression of
TNF.alpha. (panel A) and CCL2 (panel B) measured in liver samples
obtained from animals in control group 1 (C1), control group 2
(C2), test group dosed with Compound A (CpdA) and test group dosed
with Compound B (CpdB), expressed as Normalised Relative Quantity
scaled versus disease; *** means p<0.001, (*) means p<0.05
and biological trend (i.e., 0.5<NRQ-scaled<0.7 or
1.4<NRQ-scaled<2).
[0178] FIG. 10 relates to example 3.3 and shows non-alcoholic fatty
liver disease activity scoring (NAS) data from animals in control
group 1 (C1), control group 2 (C2), test group dosed with Compound
A (CpdA) and test group dosed with Compound B (CpdB); panel
A--steatosis score, panel B--ballooning score, panel
C--inflammation score, panel D total NAS score; *** means
p<0.001 versus control group 2.
[0179] FIG. 11 relates to example 3.4 and shows the fibrotic area
fraction [%] observed in liver samples obtained from animals in
control group 1 (C1), control group 2 (C2; after 8 weeks and after
10 weeks), test group dosed with Compound A (CpdA) and test group
dosed with elafibranor (CpdC); * means p<0.05, *** means
p<0.001.
[0180] FIG. 12 relates to example 3.4 and shows data on gene
expression of CollA1 (panel A) and TNF.alpha. (panel B) as measured
in samples obtained from animals in control group 1 (C1), control
group 2 (C2; after 8 weeks and after 10 weeks), test group dosed
with Compound A (CpdA) and test group dosed with elafibranor
(CpdC), expressed as Normalised Relative Quantity scaled versus
disease; * means p<0.05, ** means p<0.01, *** means
p<0.001.
[0181] FIG. 13 relates to example 3.5 and shows average .+-.s.e.m.
Ashcroft scores with Matsuse's modification after 2 week dosing
period initiated 1 week after bleomycin instillation for animals in
control group 1 (Intact; sham), control group 2 (BLM; vehicle),
control group 3 dosed with nintedanib at 60 mg/kg q.d. (BLM
nintedanib) and test group dosed with Compound A at 30 mg/kg b.i.d.
(BLM CpdA); * means p<0.05 versus BLM vehicle group.
[0182] FIG. 14 relates to example 3.5 and shows Pressure-Volume
loop perturbation after 2 week dosing period initiated 1 week after
bleomycin instillation for animals in control group 1 (Intact;
sham), control group 2 (BLM; vehicle), control group 3 dosed with
nintedanib at 60 mg/kg q.d. (BLM nintedanib) and test group dosed
with Compound A at 30 mg/kg b.i.d. (BLM CpdA); panel A--average
.+-.s.e.m. Inspiratory Capacity (mL), panel B--average .+-.s.e.m.
Compliance of the Respiratory System (mL/cmH.sub.2O), panel
C--average .+-.s.e.m. Elastance of the Respiratory System
(cmH.sub.2O/mL); * means p<0.05, ** means p<0.01, *** means
p<0.001, ns means not statistically significant versus BLM
vehicle group.
[0183] FIG. 15 relates to example 3.6 and shows collagen deposition
induced by irradiation as type I collagen stained area fraction [%]
in microscopical images of irradiated mouse lung post
immunostaining for animals in control group 1 (Sham), control group
2 (Irradiated; vehicle), control group 3 dosed with nintedanib at
60 mg/kg q.d. (Irradiated nintedanib) and test group dosed with
Compound A at 30 mg/kg q.d. (Irradiated CpdA); * means p<0.05,
** means p<0.01, *** means p<0.001 versus the Irradiated
vehicle group.
[0184] FIG. 16 relates to example 3.6 and shows MnSOD stained area
fraction [%] in microscopical images of irradiated mouse lung post
immunostaining for animals in control group 1 (Sham), control group
2 (Irradiated; vehicle), control group 3 dosed with nintedanib at
60 mg/kg q.d. (Irradiated nintedanib) and test group dosed with
Compound A at 30 mg/kg q.d. (Irradiated CpdA); ** means p<0.01,
*** means p<0.001 versus the Irradiated vehicle group.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0185] The following terms are intended to have the meanings
presented therewith below and are useful in understanding the
description and intended scope of the present invention.
[0186] When describing the invention, which may include compounds,
pharmaceutical compositions containing such compounds and methods
of using such compounds and compositions, the following terms, if
present, have the following meanings unless otherwise indicated. It
should also be understood that when described herein any of the
moieties defined forth below may be substituted with a variety of
substituents, and that the respective definitions are intended to
include such substituted moieties within their scope as set out
below. Unless otherwise stated, the term "substituted" is to be
defined as set out below. It should be further understood that the
terms "groups" and "radicals" can be considered interchangeable
when used herein.
[0187] The articles `a` and `an` may be used herein to refer to one
or to more than one (i.e. at least one) of the grammatical objects
of the article. By way of example `an analogue` means one analogue
or more than one analogue.
[0188] `Alkyl` means straight or branched aliphatic hydrocarbon
having the specified number of carbon atoms. Particular alkyl
groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched
means that one or more alkyl groups such as methyl, ethyl or propyl
is attached to a linear alkyl chain Particular alkyl groups are
methyl (--CH.sub.3), ethyl (--CH.sub.2--CH.sub.3), n-propyl
(--CH.sub.2--CH.sub.2--CH.sub.3), isopropyl (--CH(CH.sub.3).sub.2),
n-butyl (--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), tert-butyl
(--CH.sub.2--C(CH.sub.3).sub.3), sec-butyl
(--CH.sub.2--CH(CH.sub.3).sub.2), n-pentyl
(--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), n-hexyl
(--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), and
1,2-dimethylbutyl
(--CHCH.sub.3)--C(CH.sub.3)H.sub.2--CH.sub.2--CH.sub.3). Particular
alkyl groups have between 1 and 4 carbon atoms.
[0189] `Alkenyl` refers to monovalent olefinically (unsaturated)
hydrocarbon groups with the number of carbon atoms specified.
Particular alkenyl has 2 to 8 carbon atoms, and more particularly,
from 2 to 6 carbon atoms, which can be straight-chained or branched
and having at least 1 and particularly from 1 to 2 sites of
olefinic unsaturation. Particular alkenyl groups include ethenyl
(--CH.dbd.CH.sub.2), n-propenyl (--CH.sub.2CH.dbd.CH.sub.2),
isopropenyl (--C(CH.sub.3).dbd.CH.sub.2) and the like.
[0190] `Alkylene` refers to divalent alkene radical groups having
the number of carbon atoms specified, in particular having 1 to 6
carbon atoms and more particularly 1 to 4 carbon atoms which can be
straight-chained or branched. This term is exemplified by groups
such as methylene (--CH.sub.2--), ethylene
(--CH.sub.2--CH.sub.2--), or --CH(CH.sub.3)-- and the like.
[0191] `Alkynylene` refers to divalent alkyne radical groups having
the number of carbon atoms and the number of triple bonds
specified, in particular 2 to 6 carbon atoms and more particularly
2 to 4 carbon atoms which can be straight-chained or branched. This
term is exemplified by groups such as --C.ident.C--,
--CH.sub.2--C.ident.C--, and --C(CH.sub.3)H--C.ident.CH--.
[0192] `Alkoxy` refers to the group O-alkyl, where the alkyl group
has the number of carbon atoms specified. In particular the term
refers to the group --O--C.sub.1-6 alkyl. Particular alkoxy groups
are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy,
sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular
alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon
atoms. Further particular alkoxy groups have between 1 and 4 carbon
atoms.
[0193] `Amino` refers to the radical --NH.sub.2.
[0194] `Aryl` refers to a monovalent aromatic hydrocarbon group
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. In particular aryl refers to
an aromatic ring structure, monocyclic or fused polycyclic, with
the number of ring atoms specified. Specifically, the term includes
groups that include from 6 to 10 ring members. Particular aryl
groups include phenyl, and naphthyl.
[0195] `Cycloalkyl` refers to a non-aromatic hydrocarbyl ring
structure, monocyclic, fused polycyclic, bridged polycyclic, or
spirocyclic, with the number of ring atoms specified. A cycloalkyl
may have from 3 to 12 carbon atoms, in particular from 3 to 10, and
more particularly from 3 to 7 carbon atoms. Such cycloalkyl groups
include, by way of example, single ring structures such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl.
[0196] `Cyano` refers to the radical --CN.
[0197] `Halo` or `halogen` refers to fluoro (F), chloro (Cl), bromo
(Br) and iodo (I). Particular halo groups are either fluoro or
chloro.
[0198] `Hetero` when used to describe a compound or a group present
on a compound means that one or more carbon atoms in the compound
or group have been replaced by a nitrogen, oxygen, or sulfur
heteroatom. Hetero may be applied to any of the hydrocarbyl groups
described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g.
heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1
to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or
2 heteroatoms, for example a single heteroatom.
[0199] `Heteroaryl` means an aromatic ring structure, monocyclic or
fused polycyclic, that includes one or more heteroatoms
independently selected from O, N and S and the number of ring atoms
specified. In particular, the aromatic ring structure may have from
5 to 9 ring members. The heteroaryl group can be, for example, a
five membered or six membered monocyclic ring or a fused bicyclic
structure formed from fused five and six membered rings or two
fused six membered rings or, by way of a further example, two fused
five membered rings. Each ring may contain up to four heteroatoms
typically selected from nitrogen, sulphur and oxygen. Typically the
heteroaryl ring will contain up to 4 heteroatoms, more typically up
to 3 heteroatoms, more usually up to 2, for example a single
heteroatom. In one embodiment, the heteroaryl ring contains at
least one ring nitrogen atom. The nitrogen atoms in the heteroaryl
rings can be basic, as in the case of an imidazole or pyridine, or
essentially non-basic as in the case of an indole or pyrrole
nitrogen. In general the number of basic nitrogen atoms present in
the heteroaryl group, including any amino group substituents of the
ring, will be less than five.
[0200] Examples of five membered monocyclic heteroaryl groups
include but are not limited to pyrrolyl, furanyl, thiophenyl,
imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl,
isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and
tetrazolyl groups.
[0201] Examples of six membered monocyclic heteroaryl groups
include but are not limited to pyridinyl, pyrazinyl, pyridazinyl,
pyrimidinyl and triazinyl.
[0202] Particular examples of bicyclic heteroaryl groups containing
a five membered ring fused to another five-membered ring include
but are not limited to imidazothiazolyl and imidazoimidazolyl.
[0203] Particular examples of bicyclic heteroaryl groups containing
a six membered ring fused to a five membered ring include but are
not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl,
benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl,
indolizinyl, purinyl (e.g. adenine, guanine), indazolyl,
pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl
groups.
[0204] Particular examples of bicyclic heteroaryl groups containing
two fused six membered rings include but are not limited to
quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl,
quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and
pteridinyl groups. Particular heteroaryl groups are those derived
from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl,
pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
[0205] Examples of representative heteroaryls include the
following:
##STR00007##
wherein each Y is selected from >C.dbd.O, NH, O and S.
[0206] `Heterocycloalkyl` means a non-aromatic fully saturated ring
structure, monocyclic, fused polycyclic, spirocyclic, or bridged
polycyclic, that includes one or more heteroatoms independently
selected from O, N and S and the number of ring atoms specified.
The heterocycloalkyl ring structure may have from 4 to 12 ring
members, in particular from 4 to 10 ring members and more
particularly from 4 to 7 ring members. Each ring may contain up to
four heteroatoms typically selected from nitrogen, sulphur and
oxygen. Typically the heterocycloalkyl ring will contain up to 4
heteroatoms, more typically up to 3 heteroatoms, more usually up to
2, for example a single heteroatom. Examples of heterocyclic rings
include, but are not limited to azetidinyl, oxetanyl, thietanyl,
pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and
3-pyrrolidinyl), tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl,
2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothiophenyl
(e.g. 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl and
3-tetrahydrothiophenyl), piperidinyl (e.g. 1-piperidinyl,
2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl
(e.g. 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g.
4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl,
or piperazinyl.
[0207] As used herein, the term `heterocycloalkenyl` means a
`heterocycloalkyl`, which comprises at least one double bond.
Particular examples of heterocycloalkenyl groups are shown in the
following illustrative examples:
##STR00008##
wherein each W is selected from CH.sub.2, NH, O and S; each Y is
selected from NH, O, C(.dbd.O), SO.sub.2, and S; and each Z is
selected from N or CH.
[0208] Particular examples of monocyclic rings are shown in the
following illustrative examples:
##STR00009##
wherein each W and Y is independently selected from --CH.sub.2--,
--NH--, --O-- and --S--.
[0209] Particular examples of fused bicyclic rings are shown in the
following illustrative examples:
##STR00010##
wherein each W and Y is independently selected from --CH.sub.2--,
--NH--, --O-- and --S--.
[0210] Particular examples of bridged bicyclic rings are shown in
the following illustrative examples:
##STR00011##
wherein each W and Y is independently selected from --CH.sub.2--,
--NH--, --O-- and --S-- and each Z is selected from N or CH.
[0211] Particular examples of spirocyclic rings are shown in the
following illustrative examples:
##STR00012##
wherein each Y is selected from --CH.sub.2--, --NH--, --O-- and
--S--.
[0212] `Hydroxyl` refers to the radical --OH.
[0213] `Oxo` refers to the radical .dbd.O.
[0214] `Substituted` refers to a group in which one or more
hydrogen atoms are each independently replaced with the same or
different substituent(s).
[0215] `Sulfo` or `sulfonic acid` refers to a radical such as
--SO.sub.3H.
[0216] `Thiol` refers to the group --SH.
[0217] As used herein, term `substituted with one or more` refers
to one to four substituents. In one embodiment it refers to one to
three substituents. In further embodiments it refers to one or two
substituents. In a yet further embodiment it refers to one
substituent.
[0218] `Thioalkoxy` refers to the group S-alkyl where the alkyl
group has the number of carbon atoms specified. In particular the
term refers to the group --S--C.sub.1-6 alkyl. Particular
thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy,
isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, sec-thiobutoxy,
n-thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy. Particular
thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6
carbon atoms. Further particular alkoxy groups have between 1 and 4
carbon atoms.
[0219] One having ordinary skill in the art of organic synthesis
will recognize that the maximum number of heteroatoms in a stable,
chemically feasible heterocyclic ring, whether it is aromatic or
non-aromatic, is determined by the size of the ring, the degree of
unsaturation and the valence of the heteroatoms. In general, a
heterocyclic ring may have one to four heteroatoms so long as the
heteroaromatic ring is chemically feasible and stable.
[0220] `Pharmaceutically acceptable` means approved or approvable
by a regulatory agency of the Federal or a state government or the
corresponding agency in countries other than the United States, or
that is listed in the U.S. Pharmacopoeia or other generally
recognized pharmacopoeia for use in animals, and more particularly,
in humans.
[0221] `Pharmaceutically acceptable salt` refers to a salt of a
compound of the invention that is pharmaceutically acceptable and
that possesses the desired pharmacological activity of the parent
compound. In particular, such salts are non-toxic may be inorganic
or organic acid addition salts and base addition salts.
Specifically, such salts include: (1) acid addition salts, formed
with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g. an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine and the like.
Salts further include, by way of example only, sodium, potassium,
calcium, magnesium, ammonium, tetraalkylammonium, and the like; and
when the compound contains a basic functionality, salts of
non-toxic organic or inorganic acids, such as hydrochloride,
hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the
like. The term `pharmaceutically acceptable cation` refers to an
acceptable cationic counter-ion of an acidic functional group. Such
cations are exemplified by sodium, potassium, calcium, magnesium,
ammonium, tetraalkylammonium cations, and the like.
[0222] `Pharmaceutically acceptable vehicle` refers to a diluent,
adjuvant, excipient or carrier with which a compound of the
invention is administered.
[0223] `Prodrugs` refers to compounds, including derivatives of the
compounds of the invention, which have cleavable groups and become
by solvolysis or under physiological conditions the compounds of
the invention which are pharmaceutically active in vivo. Such
examples include, but are not limited to, choline ester derivatives
and the like, N-alkylmorpholine esters and the like.
[0224] `Solvate` refers to forms of the compound that are
associated with a solvent, usually by a solvolysis reaction. This
physical association includes hydrogen bonding. Conventional
solvents include water, EtOH, acetic acid and the like. The
compounds of the invention may be prepared e.g. in crystalline form
and may be solvated or hydrated. Suitable solvates include
pharmaceutically acceptable solvates, such as hydrates, and further
include both stoichiometric solvates and non-stoichiometric
solvates. In certain instances the solvate will be capable of
isolation, for example when one or more solvent molecules are
incorporated in the crystal lattice of the crystalline solid.
`Solvate` encompasses both solution-phase and isolable solvates.
Representative solvates include hydrates, ethanolates and
methanolates.
[0225] `Subject` includes humans. The terms `human`, `patient` and
`subject` are used interchangeably herein.
[0226] `Effective amount` means the amount of a compound of the
invention that, when administered to a subject for treating a
disease, is sufficient to effect such treatment for the disease.
The "effective amount" can vary depending on the compound, the
disease and its severity, and the age, weight, etc., of the subject
to be treated.
[0227] `Preventing` or `prevention` refers to a reduction in risk
of acquiring or developing a disease or disorder (i.e. causing at
least one of the clinical symptoms of the disease not to develop in
a subject that may be exposed to a disease-causing agent, or
predisposed to the disease in advance of disease onset.
[0228] The term `prophylaxis` is related to `prevention`, and
refers to a measure or procedure the purpose of which is to
prevent, rather than to treat or cure a disease. Non-limiting
examples of prophylactic measures may include the administration of
vaccines; the administration of low molecular weight heparin to
hospital patients at risk for thrombosis due, for example, to
immobilization; and the administration of an anti-malarial agent
such as chloroquine, in advance of a visit to a geographical region
where malaria is endemic or the risk of contracting malaria is
high.
[0229] `Treating` or `treatment` of any disease or disorder refers,
in one embodiment, to ameliorating the disease or disorder (i.e.
arresting the disease or reducing the manifestation, extent or
severity of at least one of the clinical symptoms thereof). In
another embodiment `treating` or `treatment` refers to ameliorating
at least one physical parameter, which may not be discernible by
the subject. In yet another embodiment, `treating` or `treatment`
refers to modulating the disease or disorder, either physically,
(e.g. stabilization of a discernible symptom), physiologically,
(e.g. stabilization of a physical parameter), or both. In a further
embodiment, "treating" or "treatment" relates to slowing the
progression of the disease.
[0230] As used herein the term `fibrotic diseases` refers to
diseases characterized by excessive scarring due to excessive
production, deposition, and contraction of extracellular matrix,
and are that are associated with the abnormal accumulation of cells
and/or fibronectin and/or collagen and/or increased fibroblast
recruitment and include but are not limited to fibrosis of
individual organs or tissues such as the heart, kidney, liver,
joints, lung, pleural tissue, peritoneal tissue, skin, cornea,
retina, musculoskeletal and digestive tract. In particular, the
term fibrotic diseases refers to idiopathic pulmonary fibrosis
(IPF); cystic fibrosis, other diffuse parenchymal lung diseases of
different etiologies including iatrogenic drug-induced fibrosis,
occupational and/or environmental induced fibrosis, granulomatous
diseases (sarcoidosis, hypersensitivity pneumonia), collagen
vascular disease, alveolar proteinosis, Langerhans cell
granulomatosis, lymphangioleiomyomatosis, inherited diseases
(Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis,
metabolic storage diseases, familial interstitial lung disease);
radiation induced fibrosis; chronic obstructive pulmonary disease;
scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma;
silicosis; asbestos induced pulmonary fibrosis; acute respiratory
distress syndrome (ARDS); kidney fibrosis; tubulointerstitium
fibrosis; glomerular nephritis; diabetic nephropathy, focal
segmental glomerular sclerosis; IgA nephropathy; hypertension;
Alport; gut fibrosis; liver fibrosis; cirrhosis; alcohol induced
liver fibrosis; toxic/drug induced liver fibrosis; hemochromatosis;
alcoholic steato hepatitis (ASH), nonalcoholic steatohepatitis
(NASH), nonalcoholic fatty liver disease (NAFLD); cholestasis,
biliary duct injury; primary sclerosing cholangitis (PSC), primary
biliary cirrhosis (PBC); infection induced liver fibrosis; viral
induced liver fibrosis; and autoimmune hepatitis; corneal scarring;
hypertrophic scarring; Dupuytren disease, keloids, cutaneous
fibrosis; cutaneous scleroderma; systemic sclerosis, spinal cord
injury/fibrosis; myelofibrosis; Duchenne muscular dystrophy (DMD)
associated musculoskeletal fibrosis, vascular restenosis;
atherosclerosis; arteriosclerosis; Wegener's granulomatosis;
Peyronie's disease, or chronic lymphocytic. More particularly, the
term "fibrotic diseases" refers to idiopathic pulmonary fibrosis
(IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH),
nonalcoholic fatty liver disease (NAFLD), Alcoholic steato
hepatitis, (ASH), portal hypertension, systemic sclerosis, renal
fibrosis, and cutaneous fibrosis. Most particularly, the term
"fibrotic diseases" refers to nonalcoholic steatohepatitis (NASH),
and/or nonalcoholic fatty liver disease (NAFLD). Alternatively,
most particularly, the term "fibrotic diseases" refers to IPF.
[0231] `Compound(s) of the invention`, and equivalent expressions,
are meant to embrace compounds of the Formula(e) as herein
described, which expression includes the pharmaceutically
acceptable salts, and the solvates, e.g. hydrates, and the solvates
of the pharmaceutically acceptable salts where the context so
permits. Similarly, reference to intermediates, whether or not they
themselves are claimed, is meant to embrace their salts, and
solvates, where the context so permits.
[0232] When ranges are referred to herein, for example but without
limitation, C.sub.1-8 alkyl, the citation of a range should be
considered a representation of each member of said range.
[0233] Other derivatives of the compounds of this invention have
activity in both their acid and acid derivative forms, but in the
acid sensitive form often offers advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism
(Bundgard, H, 1985). Prodrugs include acid derivatives well know to
practitioners of the art, such as, for example, esters prepared by
reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides and anhydrides derived
from acidic groups pendant on the compounds of this invention are
particularly useful prodrugs. In some cases it is desirable to
prepare double ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.6-10 optionally
substituted aryl, and (C.sub.6-10 aryl)-(C.sub.1-4 alkyl) esters of
the compounds of the invention.
[0234] The present disclosure includes all isotopic forms of the
compounds of the invention provided herein, whether in a form (i)
wherein all atoms of a given atomic number have a mass number (or
mixture of mass numbers) which predominates in nature (referred to
herein as the "natural isotopic form") or (ii) wherein one or more
atoms are replaced by atoms having the same atomic number, but a
mass number different from the mass number of atoms which
predominates in nature (referred to herein as an "unnatural variant
isotopic form"). It is understood that an atom may naturally exists
as a mixture of mass numbers. The term "unnatural variant isotopic
form" also includes embodiments in which the proportion of an atom
of given atomic number having a mass number found less commonly in
nature (referred to herein as an "uncommon isotope") has been
increased relative to that which is naturally occurring e.g. to the
level of >20%, >50%, >75%, >90%, >95% or >99% by
number of the atoms of that atomic number (the latter embodiment
referred to as an "isotopically enriched variant form"). The term
"unnatural variant isotopic form" also includes embodiments in
which the proportion of an uncommon isotope has been reduced
relative to that which is naturally occurring. Isotopic forms may
include radioactive forms (i.e. they incorporate radioisotopes) and
non-radioactive forms. Radioactive forms will typically be
isotopically enriched variant forms.
[0235] An unnatural variant isotopic form of a compound may thus
contain one or more artificial or uncommon isotopes such as
deuterium (.sup.2H or D), carbon-11 (.sup.11C), carbon-13
(.sup.13C), carbon-14 (.sup.14C), nitrogen-13 (.sup.13N),
nitrogen-15 (.sup.15N), oxygen-15 (.sup.15O), oxygen-17 (.sup.17O),
oxygen-18 (.sup.18O), phosphorus-32 (.sup.32P), sulphur-35
(.sup.35S), chlorine-36 (.sup.36Cl), chlorine-37 (.sup.37Cl),
fluorine-18 (.sup.18F) iodine-123 (.sup.123I), iodine-125
(.sup.125I) in one or more atoms or may contain an increased
proportion of said isotopes as compared with the proportion that
predominates in nature in one or more atoms.
[0236] Unnatural variant isotopic forms comprising radioisotopes
may, for example, be used for drug and/or substrate tissue
distribution studies. The radioactive isotopes tritium, i.e.
.sup.3H, and carbon-14, i.e. .sup.14C, are particularly useful for
this purpose in view of their ease of incorporation and ready means
of detection. Unnatural variant isotopic forms which incorporate
deuterium i.e .sup.2H or D may afford certain therapeutic
advantages resulting from greater metabolic stability, for example,
increased in vivo half-life or reduced dosage requirements, and
hence may be preferred in some circumstances. Further, unnatural
variant isotopic forms may be prepared which incorporate positron
emitting isotopes, such as .sup.11C, .sup.18F, .sup.15O and
.sup.13N, a N, and would be useful in Positron Emission Topography
(PET) studies for examining substrate receptor occupancy.
[0237] It is also to be understood that compounds that have the
same molecular formula but differ in the nature or sequence of
bonding of their atoms or the arrangement of their atoms in space
are termed `isomers`. Isomers that differ in the arrangement of
their atoms in space are termed `stereoisomers`.
[0238] Stereoisomers that are not mirror images of one another are
termed `diastereomers` and those that are non-superimposable mirror
images of each other are termed `enantiomers`. When a compound has
an asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a `racemic mixture`.
[0239] `Tautomers` refer to compounds that are interchangeable
forms of a particular compound structure, and that vary in the
displacement of hydrogen atoms and electrons. Thus, two structures
may be in equilibrium through the movement of .pi. electrons and an
atom (usually H). For example, enols and ketones are tautomers
because they are rapidly interconverted by treatment with either
acid or base. Another example of tautomerism is the aci- and
nitro-forms of phenylnitromethane that are likewise formed by
treatment with acid or base.
[0240] Tautomeric forms may be relevant to the attainment of the
optimal chemical reactivity and biological activity of a compound
of interest.
[0241] The compounds of the invention may possess one or more
asymmetric centers; such compounds can therefore be produced as
individual (R)- or (S)-stereoisomers or as mixtures thereof.
[0242] Unless indicated otherwise, the description or naming of a
particular compound in the specification and claims is intended to
include both individual enantiomers and mixtures, racemic or
otherwise, thereof. The methods for the determination of
stereochemistry and the separation of stereoisomers are well-known
in the art.
[0243] It will be appreciated that compounds of the invention may
be metabolized to yield biologically active metabolites.
THE INVENTION
[0244] The present invention relates to compounds useful in the
prophylaxis and/or treatment of one or more fibrotic diseases. In
particular, it has been identified that the compounds of the
invention which antagonize GPR84, a G-protein-coupled receptor may
useful in the prophylaxis and/or treatment of one or more fibrotic
diseases. The present invention also provides pharmaceutical
compositions comprising the compounds for use and methods for the
prophylaxis and/or treatment of one or more fibrotic diseases by
administering said compound.
[0245] Accordingly, in a first aspect of the invention, are
provided compounds having GPR84 antagonist activity for use in the
prophylaxis and/or treatment of one or more fibrotic diseases.
[0246] In a particular aspect, are provided the compounds of
Formula I, II, III, and IV, respectively disclosed in WO
2013/092791, WO 2014/095798, WO 2015/197550, and WO 2016/169911 the
entire disclosure being incorporated herein by reference for use in
the prophylaxis and/or treatment of one or more fibrotic
diseases.
[0247] The compounds of Formula I are shown below:
##STR00013##
wherein R.sup.1 is H, Me, or halo; L.sub.1 is absent or is --O--,
--S--, or --NR.sup.4a--;
G is
[0248] R.sup.2, [0249] --W-L.sub.2-R.sup.2, or [0250]
--W-L.sub.3-R.sup.3; W is C.sub.1-4 alkylene, C.sub.2-4 alkenylene
having one double bond, or C.sub.2-4 alkynylene having one triple
bond; L.sub.2 is absent or is --O--;
R.sup.2 is
[0250] [0251] H, [0252] C.sub.1-8 alkyl, optionally substituted
with one to three groups independently selected from [0253] OH,
[0254] halo, [0255] CN, [0256] C.sub.1-6 alkoxy, [0257] C.sub.3-7
cycloalkyl, [0258] 4-6 membered heterocycloalkyl comprising one to
three heteroatoms independently selected from S, and O, [0259] 5-6
membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O, and [0260] phenyl, [0261]
C.sub.4-7 cycloalkenyl comprising one double bond, [0262] 5-7
membered heterocycloalkenyl comprising one double bond, and one to
three heteroatoms independently selected from N, O, and S, [0263]
C.sub.3-7 cycloalkyl optionally substituted with one or more
independently selected R.sup.5 groups, [0264] 4-10 membered
heterocycloalkyl comprising one to two heteroatoms independently
selected from S, and O, optionally substituted with one to three
independently selected R.sup.5 groups, [0265] 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O, optionally substituted with one to three
independently selected R.sup.6 groups, or [0266] C.sub.6-10 aryl
optionally substituted with one or more independently selected
R.sup.6 groups; L.sub.3 is --NR.sup.4b--;
R.sup.3 is
[0266] [0267] C.sub.1-4 alkyl substituted with [0268] C.sub.6-10
aryl optionally substituted with one or more independently selected
R.sup.7 groups, or [0269] 5-10 membered heteroaryl comprising one
to three heteroatoms independently selected from N, S, and O,
optionally substituted with one or more independently selected
R.sup.7 groups, [0270] 5-10 membered heteroaryl comprising one to
three heteroatoms independently selected from N, S, and O,
optionally substituted with one or more independently selected
R.sup.7 groups, or [0271] C.sub.6-10 aryl optionally substituted
with one or more independently selected R.sup.7 groups; Each
R.sup.4a and R.sup.4b is independently selected from H, C.sub.1-4
alkyl, and C.sub.3-7 cycloalkyl; R.sup.5 is oxo or R.sup.6;
R.sup.6 is
[0271] [0272] OH, [0273] halo, [0274] --NO.sub.2, [0275] C.sub.1-6
alkyl optionally substituted with one to three groups independently
selected from halo, and OH, [0276] C.sub.1-6 alkoxy optionally
substituted with one to three groups independently selected from
halo, and OH, [0277] C.sub.3-7 cycloalkyl, [0278]
--C(.dbd.O)OR.sup.8, [0279] --C(.dbd.O)NR.sup.9R.sup.10, [0280]
--NHC(.dbd.O)--C.sub.1-4 alkyl, [0281] --CN, [0282] phenyl, [0283]
--O-phenyl, [0284] 4-7 membered heterocycloalkyl comprising one to
three heteroatoms independently selected from N, O, and S, or
[0285] 5-6 membered heteroaryl comprising one to three heteroatoms
independently selected from N, O, and S; optionally substituted
with one or more independently selected C.sub.1-4 alkyl, C.sub.1-4
alkoxy, CN, halo, and --C(.dbd.O)OR.sup.11; R.sup.7 is C.sub.1-4
alkyl, or halo, and each of R.sup.8, R.sup.9, R.sup.10 and R.sup.11
is independently selected from H and C.sub.1-4 alkyl.
[0286] In one embodiment, the compound according to Formula I is
according to anyone of Formula I.Ia-I.Id:
##STR00014##
wherein R.sup.2 is as described previously.
[0287] In one embodiment, the compound according to Formula I is
according to any one of Formula I.IIa-I.IId:
##STR00015##
wherein R.sup.2 is as described previously.
[0288] In one embodiment, the compound according to Formula I is
according to any one of Formula I.IIIa-I.IIId:
##STR00016##
wherein R.sup.2 is as described previously.
[0289] In one embodiment, the compound of the invention is
according to anyone of Formula I.Ia, I.Ib, I.IIa, I.IIb, I.IIIa, or
I.IIIb, wherein R.sup.2 is C.sub.3-7 cycloalkyl. In a preferred
embodiment, R.sup.2 is cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl. In a more preferred embodiment, R.sup.2 is
cyclopropyl.
[0290] In one embodiment, the compound of the invention is
according to anyone of Formula I.Ia, I.Ib, I.IIa, I.IIb, I.IIIa, or
I.IIIb, wherein R.sup.2 is not C.sub.3-7 cycloalkyl. In a preferred
embodiment, R.sup.2 is not cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl. In a more preferred embodiment, R.sup.2 is not
cyclopropyl.
[0291] In one embodiment, the compound of the invention is
according to anyone of Formula I.Ia, I.Ib, I.IIa, I.IIb, I.IIIa, or
I.IIIb, wherein R.sup.2 is C.sub.3-7 cycloalkyl substituted with
one to three independently selected R.sup.5 groups. In a preferred
embodiment, R.sup.2 is C.sub.3-7 cycloalkyl substituted with one
R.sup.5 group. In a more preferred embodiment, R.sup.2 is
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which
is substituted with one R.sup.5 group. In another more preferred
embodiment, R.sup.2 is C.sub.3-7 cycloalkyl substituted with one
R.sup.5 group, wherein R.sup.5 is oxo, or R.sup.6 wherein R.sup.6
is selected from OH, or C.sub.1-6 alkyl. In a most preferred
embodiment, R.sup.2 is cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl, each of which is substituted with one R.sup.5 group,
wherein R.sup.5 is oxo, or R.sup.6 wherein R.sup.6 is selected from
OH, and C.sub.1-6 alkyl. In a further most preferred embodiment,
R.sup.2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each
of which is substituted with one R.sup.5 group, wherein R.sup.5 is
OH.
[0292] In one embodiment, the compound of the invention is
according to anyone of Formula I.Ia, I.Ib, I.IIa, I.IIb, I.IIIa, or
I.IIIb, wherein R.sup.2 is not C.sub.3-7 cycloalkyl substituted
with one to three independently selected R.sup.5 groups. In a
preferred embodiment, R.sup.2 is not C.sub.3-7 cycloalkyl
substituted with one R.sup.5 group. In a more preferred embodiment,
R.sup.2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,
each of which is substituted with one R.sup.5 group. In another
more preferred embodiment, R.sup.2 is not C.sub.3-7 cycloalkyl
substituted with one R.sup.5 group, wherein R.sup.5 is oxo, or
R.sup.6 wherein R.sup.6 is selected from OH, and C.sub.1-6 alkyl.
In a most preferred embodiment, R.sup.2 is not cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted
with one R.sup.5 group, wherein R.sup.5 is oxo, or R.sup.6 wherein
R.sup.6 is selected from OH, and C.sub.1-6 alkyl. In a further most
preferred embodiment, R.sup.2 is not cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl, each of which is substituted with one
R.sup.5 group, wherein R.sup.5 is OH.
[0293] In one embodiment, the compound of the invention is
according to Formula I.Ic, I.Id, I.IIc, I.IId, I.IIIc, or I.IIId,
wherein R.sup.2 is 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O. In a preferred
embodiment, R.sup.2 is furanyl, thienyl, oxazolyl, thiazolyl,
oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,
pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
[0294] In one embodiment, the compound of the invention is
according to Formula I.Ic, I.Id, I.IIc, I.IId, I.IIIc, or I.IIId,
wherein R.sup.2 is not 5-10 membered heteroaryl comprising one to
three heteroatoms independently selected from N, S, and O. In a
preferred embodiment, R.sup.2 is not furanyl, thienyl, oxazolyl,
thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
[0295] In another embodiment, the compound of the invention is
according to Formula I.Ic, I.Id, I.IIc, I.IId, I.IIIc, or I.IIId,
wherein R.sup.2 is 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, substituted
with one to three independently selected R.sup.6 groups. In a
preferred embodiment, R.sup.2 is 5-10 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
S, and O, substituted with one or two independently selected
R.sup.6 groups. In a more preferred embodiment, R.sup.2 is furanyl,
thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,
imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl,
or indazolyl, substituted with one or two independently selected
R.sup.6 groups. In another more preferred embodiment, R.sup.2 is
5-10 membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O, substituted with one or
two independently selected R.sup.6 groups, wherein each R.sup.6 is
independently selected from OH, halo, C.sub.1-6 alkyl, C.sub.1-6
alkyl substituted with one or more halo, C.sub.1-6 alkoxy, --CN,
C.sub.3-7 cycloalkyl, 4-7 membered heterocycloalkyl comprising one
to three heteroatoms independently selected from N, O, and S, and
phenyl. In a most preferred embodiment, R.sup.2 is furanyl,
thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,
imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl,
or indazolyl, each of which is substituted with one or two
independently selected R.sup.6 groups, wherein each R.sup.6 is
independently selected from OH, halo, C.sub.1-6 alkyl, C.sub.1-6
alkyl substituted with one or more halo, C.sub.1-6 alkoxy, --CN,
C.sub.3-7 cycloalkyl, 4-7 membered heterocycloalkyl comprising one
to three heteroatoms independently selected from N, O, and S, and
phenyl. In another most preferred embodiment, R.sup.2 is 5-10
membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O, substituted with one or
two independently selected R.sup.6 groups, wherein each R.sup.6 is
independently selected from OH, F, Cl, Me, Et, Pr, i-Pr, t-Bu,
--CF.sub.3, --OMe, --OEt, Oi-Pr, --CN, cyclopropyl, pyrrolidinyl,
morpholinyl, piperidinyl, and phenyl. In a further most preferred
embodiment, R.sup.2 is furanyl, thienyl, oxazolyl, thiazolyl,
oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,
pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is
substituted with one or two independently selected R.sup.6 groups,
wherein each R.sup.6 is independently selected from OH, F, Cl, Me,
Et, Pr, i-Pr, t-Bu, --CF.sub.3, --OMe, --OEt, --Oi-Pr, --CN,
cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and
phenyl.
[0296] In another embodiment, the compound of the invention is
according to Formula I.Ic, I.Id, I.IIc, I.IId, I.IIIc, or I.IIId,
wherein R.sup.2 is not 5-10 membered heteroaryl comprising one to
three heteroatoms independently selected from N, S, and O,
substituted with one to three independently selected R.sup.6
groups. In a preferred embodiment, R.sup.2 is not 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O, substituted with one or two
independently selected R.sup.6 groups. In a more preferred
embodiment, R.sup.2 is not furanyl, thienyl, oxazolyl, thiazolyl,
oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,
pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one
or two independently selected R.sup.6 groups. In another more
preferred embodiment, R.sup.2 is not 5-10 membered heteroaryl
comprising one to three heteroatoms independently selected from N,
S, and O, substituted with one or two independently selected
R.sup.6 groups, wherein each R.sup.6 is independently selected from
OH, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with one or
more halo, C.sub.1-6 alkoxy, --CN, C.sub.3-7 cycloalkyl, 4-7
membered heterocycloalkyl comprising one to three heteroatoms
independently selected from N, O, and S, and phenyl. In a most
preferred embodiment, R.sup.2 is not furanyl, thienyl, oxazolyl,
thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of
which is substituted with one or two independently selected R.sup.6
groups, wherein each R.sup.6 is independently selected from OH,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with one or more
halo, C.sub.1-6 alkoxy, --CN, C.sub.3-7 cycloalkyl, 4-7 membered
heterocycloalkyl comprising one to three heteroatoms independently
selected from N, O, and S, and phenyl. In another most preferred
embodiment, R.sup.2 is not 5-10 membered heteroaryl comprising one
to three heteroatoms independently selected from N, S, and O,
substituted with one or two independently selected R.sup.6 groups,
wherein each R.sup.6 is independently selected from OH, F, Cl, Me,
Et, Pr, i-Pr, t-Bu, --CF.sub.3, --OMe, --OEt, Oi-Pr, --CN,
cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl. In
a further most preferred embodiment, R.sup.2 is not furanyl,
thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,
imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl,
or indazolyl, each of which is substituted with one or two
independently selected R.sup.6 groups, wherein each R.sup.6 is
independently selected from OH, F, Cl, Me, Et, Pr, i-Pr, t-Bu,
--CF.sub.3, --OMe, --OEt, --Oi-Pr, --CN, cyclopropyl, pyrrolidinyl,
morpholinyl, piperidinyl, and phenyl.
[0297] In another embodiment, the compound of the invention is
according to Formula I.Ic, I.Id, I.IIc, I.IId, I.IIIc, or I.IIId,
wherein R.sup.2 is C.sub.6-10 aryl. In a preferred embodiment,
R.sup.2 is phenyl.
[0298] In another embodiment, the compound of the invention is
according to Formula I.Ic, I.Id, I.IIc, I.IId, I.IIIc, or I.IIId,
wherein R.sup.2 is not C.sub.6-10 aryl. In a preferred embodiment,
R.sup.2 is not phenyl.
[0299] In another embodiment, the compound of the invention is
according to Formula I.Ic, I.Id, I.IIc, I.IId, I.IIIc, or I.IIId,
wherein R.sup.2 is C.sub.6-10 aryl substituted with one or more
independently selected R.sup.6 groups. In a preferred embodiment,
R.sup.2 is C.sub.6-10 aryl substituted with one or two
independently selected R.sup.6 groups. In a more preferred
embodiment, R.sup.2 is C.sub.6-10 aryl substituted with one or two
independently selected R.sup.6 groups, wherein each R.sup.6 group
is selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and
--NHC(.dbd.O)--C.sub.1-4 alkyl. In another more preferred
embodiment, R.sup.2 is C.sub.6-10 aryl substituted with one or two
independently selected R.sup.6 groups, wherein each R.sup.6 group
is selected from --C(.dbd.O)NR.sup.9R.sup.10, and each R.sup.9 and
R.sup.10 is independently selected from H and C.sub.1-4 alkyl. In
another more preferred embodiment, R.sup.2 is phenyl substituted
with one or two independently selected R.sup.6 groups. In a most
preferred embodiment, R.sup.2 is phenyl substituted with one or two
independently selected R.sup.6 groups, wherein each R.sup.6 group
is selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and
--NHC(.dbd.O)--C.sub.1-4 alkyl. In another most preferred
embodiment, R.sup.2 is phenyl substituted with one or two
independently selected R.sup.6 groups, wherein each R.sup.6 group
is selected from --C(.dbd.O)NR.sup.9R.sup.10, and each R.sup.9 and
R.sup.10 is independently selected from H and C.sub.1-4 alkyl. In a
further most preferred embodiment R.sup.2 is phenyl substituted
with one or two independently selected R.sup.6 groups, wherein each
R.sup.6 group is selected from F, Cl, CN, Me, --OMe, --OEt, - and
--NHC(.dbd.O)Me. In a further most preferred embodiment R.sup.2 is
phenyl substituted with one or two independently selected R.sup.6
groups, wherein each R.sup.6 group is selected from
C(.dbd.O)NH.sub.2, and --C(.dbd.O)NHMe.
[0300] In another embodiment, the compound of the invention is
according to Formula I.Ic, I.Id, I.IIc, I.IId, I.IIIc, or I.IIId,
wherein R.sup.2 is not C.sub.6-10 aryl substituted with one or more
independently selected R.sup.6 groups. In a preferred embodiment,
R.sup.2 is not C.sub.6-10 aryl substituted with one or two
independently selected R.sup.6 groups. In a more preferred
embodiment, R.sup.2 is not C.sub.6-10 aryl substituted with one or
two independently selected R.sup.6 groups, wherein each R.sup.6
group is selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
and --NHC(.dbd.O)--C.sub.1-4 alkyl. In another more preferred
embodiment, R.sup.2 is not C.sub.6-10 aryl substituted with one or
two independently selected R.sup.6 groups, wherein each R.sup.6
group is selected from --C(.dbd.O)NR.sup.9R.sup.10, and each
R.sup.9 and R.sup.10 is independently selected from H and C.sub.1-4
alkyl. In another more preferred embodiment, R.sup.2 is not phenyl
substituted with one or two independently selected R.sup.6 groups.
In a most preferred embodiment, R.sup.2 is not phenyl substituted
with one or two independently selected R.sup.6 groups, wherein each
R.sup.6 group is selected from halo, CN, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, and --NHC(.dbd.O)--C.sub.1-4 alkyl. In another most
preferred embodiment, R.sup.2 is not phenyl substituted with one or
two independently selected R.sup.6 groups, wherein each R.sup.6
group is selected from --C(.dbd.O)NR.sup.9R.sup.10, and each
R.sup.9 and R.sup.10 is independently selected from H and C.sub.1-4
alkyl. In a further most preferred embodiment R.sup.2 is not phenyl
substituted with one or two independently selected R.sup.6 groups,
wherein each R.sup.6 group is selected from F, Cl, CN, Me, --OMe,
--OEt, - and --NHC(.dbd.O)Me. In a further most preferred
embodiment R.sup.2 is not phenyl substituted with one or two
independently selected R.sup.6 groups, wherein each R.sup.6 group
is selected from C(.dbd.O)NH.sub.2, and --C(.dbd.O)NHMe.
[0301] The compounds of Formula II are shown below:
##STR00017##
wherein
Cy is
##STR00018##
[0302] wherein
X is O or S;
Y is --CH.sub.2--, or S;
Z is --CH.sub.2--;
[0303] each of the subscript n, m, or p is independently selected
from 0, and 1; and A is phenyl, or 5-6-membered heteroaryl
comprising one or two N-atoms; optionally substituted with one or
more independently selected R.sup.5 groups; any one of Cy1 and Cy2
is optionally substituted by one or more independently selected
C.sub.1-4 alkyl groups; R.sup.1 is H, Me, or halo; L.sub.1 is
absent or is O--, --S--, or --NR.sup.4a--;
G is
[0304] R.sup.2, [0305] --W-L.sub.2-R.sup.2, or [0306]
--W-L.sub.3-R.sup.3; W is C.sub.1-4 alkylene, C.sub.2-4 alkenylene
having one double bond, or C.sub.2-4 alkynylene having one triple
bond; L.sub.2 is absent or is --O--;
R.sup.2 is
[0306] [0307] H, [0308] C.sub.1-8 alkyl optionally substituted with
one to three groups independently selected from [0309] OH, [0310]
halo, [0311] CN, [0312] C.sub.1-6 alkoxy, [0313] C.sub.3-7
cycloalkyl, [0314] 4-6 membered heterocycloalkyl (comprising one to
three heteroatoms independently selected from S, and O), [0315] 5-6
membered heteroaryl (comprising one to three heteroatoms
independently selected from N, S, and O), and [0316] phenyl, [0317]
C.sub.4-7 cycloalkenyl comprising one double bond, [0318] 5-7
membered heterocycloalkenyl comprising one double bond, and one to
three heteroatoms independently selected from O, and S, [0319]
C.sub.3-7 cycloalkyl (optionally substituted with one or more
independently selected R.sup.6 groups), [0320] 4-10 membered
heterocycloalkyl comprising one to two heteroatoms independently
selected from S, and O, (optionally substituted with one to three
independently selected R.sup.6 groups), [0321] 5-10 membered
heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O (optionally substituted with one to three
independently selected R.sup.7 groups), or [0322] C.sub.6-10 aryl
(optionally substituted with one or more independently selected
R.sup.7 groups); L.sub.3 is --NR.sup.4b--;
R.sup.3 is
[0322] [0323] C.sub.1-4 alkyl substituted with C.sub.6-10 aryl
(optionally substituted with one or more independently selected
R.sup.8 groups), or 5-10 membered heteroaryl comprising one to
three heteroatoms independently selected from N, S, and O,
(optionally substituted with one or more independently selected
R.sup.8 groups), [0324] 5-10 membered heteroaryl comprising one to
three heteroatoms independently selected from N, S, and O,
(optionally substituted with one or more independently selected
R.sup.8 groups), or [0325] C.sub.6-10 aryl (optionally substituted
with one or more independently selected R.sup.8 groups); each
R.sup.4a and R.sup.4b is independently selected from H, C.sub.1-4
alkyl, and C.sub.3-7 cycloalkyl; R.sup.5 is halo, C.sub.1-4 alkyl
or C.sub.1-4 alkoxy; R.sup.6 is oxo or R.sup.7;
R.sup.7 is
[0325] [0326] OH, [0327] halo, [0328] --NO.sub.2, [0329] C.sub.1-6
alkyl (optionally substituted with one to three groups
independently selected from halo, and OH), [0330] C.sub.1-6 alkoxy
(optionally substituted with one to three groups independently
selected from halo, and OH), [0331] C.sub.3-7 cycloalkyl, [0332]
--C(.dbd.O)OR.sup.9, [0333] --C(.dbd.O)NR.sup.10R.sup.11, [0334]
--NHC(.dbd.O)--C.sub.1-4 alkyl, [0335] --CN, [0336] phenyl, [0337]
--O-phenyl, [0338] 4-7 membered heterocycloalkyl comprising one to
three heteroatoms independently selected from N, O, and S, or
[0339] 5-6 membered heteroaryl comprising one to three heteroatoms
independently selected from N, O, and S; (optionally substituted
with one or more independently selected C.sub.1-4 alkyl, C.sub.1-4
alkoxy, CN, halo, and --C(.dbd.O)OR.sup.12); R.sup.8 is C.sub.1-4
alkyl, or halo; and each of R.sup.9, R.sup.10, R.sup.11 and
R.sup.12, is independently selected from H and C.sub.1-4 alkyl.
[0340] The compounds of Formula III are shown below:
##STR00019##
wherein R.sup.1 is H, C.sub.1-4 alkyl, or cyclopropyl;
L.sub.A is O or NH;
G.sub.A is:
[0341] 4-6 membered monocyclic heterocycloalkyl containing one or
two O, [0342] C.sub.3-7 monocyclic cycloalkyl, or [0343] a bicyclic
group of formula Cy:
##STR00020##
[0343] wherein A is phenyl or 5-6 membered heteroaryl containing
one or two heteroatoms independently selected from N, O and S; each
R.sup.2a and R.sup.2b are independently H or --CH.sub.3; R.sup.3 is
H, --OH or --OCH.sub.3; R.sup.4 is --CN or
-L.sub.1-W.sub.1-G.sub.1, wherein [0344] L.sub.1 is absent or O,
[0345] W.sub.1 is absent, or is C.sub.1-6 alkylene, C.sub.2-4
alkenylene having one double bond or C.sub.2-4 alkynylene having
one triple bond, each of which is optionally substituted with one
or more independently selected halo, --CN or C.sub.1-4 alkoxy,
[0346] G.sub.1 is [0347] H, [0348] --CF.sub.3, [0349]
--C(.dbd.O)--C.sub.1-4 alkyl, [0350] --S(.dbd.O).sub.2--C.sub.1-4
alkyl, optionally substituted with one or more independently
selected halo, [0351] 4-6 membered monocyclic heterocycloalkyl
containing one or two O (which heterocycloalkyl is optionally
substituted with one or more independently selected R.sup.7
groups), [0352] 6 membered monocyclic heterocycloalkenyl containing
one or two O (which heterocycloalkenyl is optionally substituted
with one or more independently selected R.sup.7 groups), [0353]
C.sub.3-7 monocyclic cycloalkyl optionally substituted with one or
more independently selected R.sup.7 groups, [0354] phenyl
optionally substituted with one or more independently selected
R.sup.7 groups, [0355] or 5-6 membered heteroaryl containing one to
four heteroatoms independently selected from N, O and S (which
heteroaryl is optionally substituted with one or more independently
selected R.sup.7 groups), each R.sup.7 is: [0356] halo, [0357]
--OH, [0358] C.sub.1-4 alkyl, C.sub.3-4 monocyclic cycloalkyl, or
C.sub.1-4 alkoxy, each of which is optionally substituted with one
or more independently selected halo; R.sup.5 is --CN or
-L.sub.2-W.sub.2-G.sub.2, wherein [0359] L.sub.2 is absent, O or S,
[0360] W.sub.2 is absent or C.sub.1-4 alkylene, optionally
substituted with one or more independently selected halo, [0361]
G.sub.2 is [0362] H, [0363] --CF.sub.3, [0364] C.sub.3-7 monocyclic
cycloalkyl (which cycloalkyl is optionally substituted with one or
more independently selected halo), [0365] phenyl, [0366] or 5-6
membered heteroaryl containing one to three heteroatoms
independently selected from N, O and S; and R.sup.6 is H, --OH or
--OCH.sub.3.
[0367] The compounds of Formula IV are shown below:
##STR00021##
wherein
L.sub.A is O, or NH;
[0368] Cy.sub.A is monocyclic 4-6 membered heterocycloalkyl,
comprising one or two O atoms; each R.sup.A is independently
selected from halo, and C.sub.1-3 alkyl; the subscript n is 0, 1 or
2; R.sup.1 is H or C.sub.1-3 alkyl; R.sup.2 is H, --OH, or
C.sub.1-3 alkoxy; R.sup.3 is H or C.sub.1-3 alkoxy;
R.sup.4 is
[0369] --CN, [0370] --OH, [0371] --O--S(.dbd.O).sub.2--C.sub.1-4
alkyl optionally substituted with one or more independently
selected halo, or [0372] -L.sub.1-W.sub.1-G.sub.1; L.sub.1 is a
direct bond, --O--, --S--, --SO.sub.2--, --C(.dbd.O)NR.sup.5a--,
--NR.sup.5bC(.dbd.O)--, or --NR.sup.5c--; R.sup.5a, R.sup.5b and
R.sup.5c are independently H or C.sub.1-4 alkyl; W.sub.1 is a
direct bond or C.sub.1-2 alkylene optionally substituted with one
or more independently selected halo;
G.sub.1 is
[0372] [0373] C.sub.3-6 cycloalkyl optionally substituted with one
or more independently selected halo, [0374] 5-6 membered heteroaryl
comprising one to four heteroatoms independently selected from N,
O, and S, which heteroaryl is optionally substituted with one or
more independently selected C.sub.1-4 alkyl, [0375] 5-7 membered
heterocycloalkenyl comprising one double bond, and one to three
heteroatoms independently selected from N, O, and S, which
heterocycloalkenyl is optionally substituted with one or more
independently selected R.sup.6, [0376] monocyclic or spiro bicyclic
4-8 membered heterocycloalkyl comprising one to three heteroatoms
independently selected from N, O, and S, which heterocycloalkyl is
optionally substituted with one or more independently selected
R.sup.6, [0377] monocyclic 4-6 membered heterocycloalkyl comprising
one to three heteroatoms independently selected from N, O, and S,
fused to one or two phenyls, [0378] C.sub.1-4 alkyl optionally
substituted with one or more independently selected halo,
--NR.sup.7aR.sup.7b, or C.sub.1-4 alkoxy, which alkoxy is
optionally substituted with one or more independently selected
halo, [0379] phenyl optionally substituted with one or more
independently selected halo or C.sub.1-4 alkoxy, which alkoxy is
optionally substituted with one or more independently selected
halo;
R.sup.6 is
[0379] [0380] halo, [0381] .dbd.O, [0382] --CN, [0383] --OH, [0384]
--C(.dbd.O)--C.sub.1-4 alkoxy optionally substituted with one or
more independently selected halo, [0385] --C(.dbd.O)--C.sub.3-4
cycloalkyl, [0386] --S(.dbd.O).sub.2--C.sub.1-4 alkyl, [0387]
C.sub.1-4 alkyl optionally substituted by one or more independently
selected C.sub.1-3 alkoxy, halo, or --OH, [0388] C.sub.1-4 alkoxy,
[0389] phenyl optionally substituted by one or more independently
selected halo, [0390] --C(.dbd.O)-monocyclic 4-6 membered
heterocycloalkyl comprising one to three heteroatoms independently
selected from N, O, and S, [0391] --C(.dbd.O)NR.sup.8aR.sup.8b, or
[0392] 5-7 membered heteroaryl comprising one to four heteroatoms
independently selected from N, O, and S, which heteroaryl is
optionally substituted with one or more independently selected
C.sub.1-4 alkyl; R.sup.7a and R.sup.7b are independently H or
C.sub.1-4 alkyl, and R.sup.8a and R.sup.8b are independently H or
C.sub.1-3 alkyl.
[0393] In one embodiment, the compound according to Formula IV is
according to Formula IV.Ia:
##STR00022##
wherein G.sub.1 is as defined above.
[0394] In one embodiment, the compound according to Formula IV is
according to Formula IV.Ib:
##STR00023##
wherein G.sub.1 is as defined above.
[0395] In one embodiment, the compound according to Formula IV is
according to Formula IV.Ia, or IV.Ib, wherein G.sub.1 is C.sub.3-6
cycloalkyl. In a particular embodiment, G.sub.1 is cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl. In a particular embodiment,
G.sub.1 is cyclopropyl, cyclobutyl, or cyclopentyl. In a more
particular embodiment, Gi is cyclopropyl.
[0396] In one embodiment, the compound according to Formula IV is
according to Formula IV.Ia, or IV.Ib, wherein G.sub.1 is C.sub.3-6
cycloalkyl substituted with one or more halo. In a particular
embodiment, G.sub.1 is cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl, each of which is substituted with one or more halo. In
a particular embodiment, Gi is cyclopropyl, cyclobutyl, or
cyclopentyl, each of which is substituted with one or more halo. In
another particular embodiment, G.sub.1 is C.sub.3-6 cycloalkyl
substituted with one or more F. In a more particular embodiment, Gi
is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of
which is substituted with one or more F. In a more particular
embodiment, G.sub.1 is cyclopropyl, cyclobutyl, or cyclopentyl,
each of which is substituted with one or more F. In a most
particular embodiment, G.sub.1 is cyclopropyl substituted with one
or more F.
[0397] In one embodiment, the compound according to Formula IV is
according to Formula IV.Ia, or IV.Ib, wherein G.sub.1 is C.sub.1-4
alkyl, substituted with one or more independently selected halo,
--NR.sup.7aR.sup.7b, or C.sub.1-4 alkoxy, which alkoxy is
optionally substituted with one or more independently selected
halo, and wherein R.sup.7a and R.sup.7b are independently H or
C.sub.1-4 alkyl. In a particular embodiment, G.sub.1 is CH.sub.3,
or --CH.sub.2CH.sub.3, each of which substituted with one or more
independently selected halo, --NR.sup.7aR.sup.7b, or C.sub.1-4
alkoxy, which alkoxy is optionally substituted with one or more
independently selected halo, and wherein R.sup.7a and R.sup.7b are
independently H or C.sub.1-4 alkyl. In another particular
embodiment, G.sub.1 is C.sub.1-4 alkyl, substituted with one or
more independently selected F, --NHCH.sub.3, --NHCH.sub.2CH.sub.3,
--N(CH.sub.3).sub.2, --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCF.sub.3,
or --OCH.sub.2CF.sub.3. In a more particular embodiment, G.sub.1 is
C.sub.1-4 alkyl, substituted with one --NHCH.sub.3,
--NHCH.sub.2CH.sub.3, --N(CH.sub.3).sub.2, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCF.sub.3, or --OCH.sub.2CF.sub.3. In a most
particular embodiment, G.sub.1 is --CF.sub.3, --CHF.sub.2,
--CH.sub.2--CHF.sub.2, --CH.sub.2--CF.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.2, or
--CH.sub.2--CH.sub.2--OCF.sub.3. In a further most particular
embodiment, G.sub.1 is CF.sub.3,
[0398] In one embodiment, the compound for use is selected from:
[0399]
9-Allyloxy-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquin-
olin-4-one, [0400]
2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-3-yl-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0401]
2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-4-yl-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0402]
2-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-benzonitrile, [0403]
3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-benzonitrile, [0404]
4-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-benzonitrile, [0405]
[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquino-
lin-9-yloxy]-acetonitrile, [0406]
2-([1,4]Dioxan-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one, [0407]
2-([1,4]Dioxan-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[-
6,1-a]isoquinolin-4-one, [0408]
9-(3,5-Dichloro-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[-
6,1-a]isoquinolin-4-one, [0409]
9-Benzofuran-2-yl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]-
isoquinolin-4-one, [0410]
2-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-indole-1-carboxylic acid tert-butyl ester, [0411]
2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-indol-2-yl)-6,7-dihydro-pyrimido[6,1-a]-
isoquinolin-4-one, [0412]
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0413]
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-trifluoromethyl-pyridin-3-yl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one, [0414]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-3H-imidazol-4-ylethynyl)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one, [0415]
9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0416]
5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-pyridine-2-carboxylic acid methylamide, [0417]
2-([1,4]Dioxan-2-ylmethoxy)-9-pent-1-ynyl-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one, [0418]
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-pyridin-2-yl-ethyl)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one, [0419]
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-pyrazin-2-yl-ethyl)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one, [0420]
2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-indol-5-yl)-6,7-dihydro-pyrimido[6,1-a]-
isoquinolin-4-one, [0421]
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one, [0422]
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0423]
2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-indazol-5-yl)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one, [0424]
2-([1,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one, [0425]
3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-benzamide, [0426]
5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-2-fluoro-benzamide, [0427]
N-{3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]iso-
quinolin-9-yl]-phenyl}-acetamide, [0428]
9-Cyclopropylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one, [0429]
2-([1,4]Dioxan-2-ylmethoxy)-9-(1-hydroxy-cyclopentylethynyl)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one, [0430]
2-([1,4]Dioxan-2-ylmethoxy)-9-pyrimidin-5-yl-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one, [0431]
9-Cyclohex-1-enyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]-
isoquinolin-4-one, [0432]
2-([1,4]Dioxan-2-ylmethoxy)-9-(1-methyl-1H-indol-5-yl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0433]
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-methyl-pyridin-3-yl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0434]
2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-2-ylethynyl-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one, [0435]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-prop-1-ynyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0436]
5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-pent-4-ynenitrile, [0437]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-1-ynyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0438]
2-([1,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-phenylethynyl)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0439]
2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-3-ylethynyl-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one, [0440]
4-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-N-methyl-benzamide, [0441]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one, [0442]
9-(2-Chloro-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one, [0443]
2-([1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-but-1-ynyl)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one, [0444]
9-(1,5-Dimethyl-1H-pyrazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one, [0445]
2-([1,4]Dioxan-2-ylmethoxy)-9-(1-methyl-1H-pyrazol-3-ylmethoxy)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one, [0446]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-[1,2,4]oxadiazol-5-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0447]
2-([1,4]Dioxan-2-ylmethoxy)-9-(4-morpholin-4-yl-phenyl)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0448]
3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-4-fluoro-benzamide, [0449]
3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-5-fluoro-benzamide, [0450]
9-(3,3-Dimethyl-but-1-ynyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0451]
2-([1,4]Dioxan-2-ylmethoxy)-9-pyridin-4-ylethynyl-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one, [0452]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-isoxazol-5-ylmethoxy)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one, [0453]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-but-1-ynyl)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one, [0454]
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0455]
2-([1,4]Dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0456]
9-(3,6-Dihydro-2H-pyran-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one, [0457]
5-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-pyridine-2-carbonitrile, [0458]
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-isopropoxy-pyridin-3-yl)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one, [0459]
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0460]
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-morpholin-4-yl-pyridin-3-yl)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one, [0461]
9-(2,3-Dimethoxy-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one, [0462]
9-(3-Chloro-2-methoxy-pyridin-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one, [0463]
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-methyl-pyridin-4-yl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0464]
3-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-isonicotinonitrile, [0465]
9-(2,5-Dimethoxy-phenyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one, [0466]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-
-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0467]
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0468]
9-(2,6-Dimethoxy-pyridin-3-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-py-
rimido[6,1-a]isoquinolin-4-one, [0469]
4-[2-([1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoqui-
nolin-9-yl]-nicotinonitrile, [0470]
9-tert-Butoxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one, [0471]
2-([1,4]Dioxan-2-ylmethoxy)-9-(2-pyrrolidin-1-yl-pyridin-3-yl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one, [0472]
2-([1,4]Dioxan-2-ylmethoxy)-9-(6-pyrrolidin-1-yl-pyridin-3-yl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one, [0473]
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-phenyl-oxazol-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0474]
9-(5-tert-Butyl-oxazol-2-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one, [0475]
9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-([1,4]dioxan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0476]
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-ethyl-[1,2,4]oxadiazol-3-ylmethoxy)-6,7--
dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0477]
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-methyl-[1,2,4]oxadiazol-3-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0478]
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-isopropyl-[1,2,4]oxadiazol-3-ylmethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0479]
9-Cyclopentylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one, [0480]
9-Cyclohexylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one, [0481]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-but-1-ynyl)-6,7-dihydro-pyrimido[-
6,1-a]isoquinolin-4-one, [0482]
2-([1,4]Dioxan-2-ylmethoxy)-9-hex-1-ynyl-6,7-dihydro-pyrimido[6,1-a]isoqu-
inolin-4-one, [0483]
9-[3-(Benzyl-methyl-amino)-prop-1-ynyl]-2-([1,4]dioxan-2-ylmethoxy)-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one, [0484]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-5-methyl-hex-1-ynyl)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one, [0485]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-but-1-ynyl)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one, [0486]
9-Cyclopropyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one, [0487]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pent-1-ynyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0488]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pent-1-ynyl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one, [0489]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pent-1-ynyl)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one, [0490]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-phenyl-but-1-ynyl)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one, [0491]
9-(3-Benzylamino-prop-1-ynyl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one, [0492]
2-([1,4]Dioxan-2-ylmethoxy)-9-[(furan-2-ylmethyl)-amino]-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0493]
2-([1,4]Dioxan-2-ylmethoxy)-9-(1-ethyl-1H-pyrazol-4-yl)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0494]
2-([1,4]Dioxan-2-ylmethoxy)-9-[1-(3-methyl-butyl)-1H-pyrazol-4-yl]-6,7-di-
hydro-pyrimido[6,1-a]isoquinolin-4-one, [0495]
2-([1,4]Dioxan-2-ylmethoxy)-9-(5-methyl-furan-2-yl)-6,7-dihydro-pyrimido[-
6,1-a]isoquinolin-4-one, [0496]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-hex-1-ynyl)-6,7-dihydro-pyrimido-
[6,1-a]isoquinolin-4-one, [0497]
9-(3,5-Dimethyl-1H-pyrazol-4-yl)-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one, [0498]
2-([1,4]Dioxan-2-ylmethoxy)-9-(1H-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one, [0499]
2-([1,4]Dioxan-2-ylmethoxy)-9-(1-propyl-1H-pyrazol-4-yl)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0500]
2-[2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]-
isoquinolin-9-yl]-benzonitrile, [0501]
2-[2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]-
isoquinolin-9-yl]-benzonitrile, [0502]
9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-((R)-1-[1,4]dioxan-2-ylm-
ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0503]
2-([1,4]Dioxan-2-ylmethoxy)-9-ethynyl-6,7-dihydro-pyrimido[6,1-a]isoquino-
lin-4-one, [0504]
2-([1,4]Dioxan-2-ylmethoxy)-9-pyrimidin-2-ylethynyl-6,7-dihydro-pyrimido[-
6,1-a]isoquinolin-4-one, [0505]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-phenylamino-prop-1-ynyl)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one, [0506]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-prop-1-ynyl)-6,7--
dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0507]
9-Cyclopentyloxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one, [0508]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pent-1-ynyl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one, [0509]
9-Cyclopropylethynyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0510]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-but-1-ynyl)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one, [0511]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-imidazol-1-yl-prop-1-ynyl)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0512]
9-(2-Cyclopropyl-ethyl)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one, [0513]
9-Cyclopentyloxymethyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0514]
2-([1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-propyl)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one, [0515]
9-Allyloxy-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one, [0516]
9-Allyloxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one, [0517]
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-yloxymethyl)-6,7--
dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0518]
2-([1,4]Dioxan-2-ylmethoxy)-9-{3-[(pyridin-3-ylmethyl)-amino]-prop-1-ynyl-
}-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0519]
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-pentyl-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0520]
9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0521]
9-(2-Cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one, [0522]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(oxetan-3-yloxymethyl)-6,7-dihydro-py-
rimido[6,1-a]isoquinolin-4-one, [0523]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methyl-oxetan-3-ylmethoxymethyl)-6-
,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0524]
9-(2,2-Dimethyl-butylamino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one, [0525]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pentyl)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one, [0526]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-ethyl-hexylamino)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0527]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-ethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0528]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-ethoxy-ethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0529]
9-Cyclopropylmethoxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0530]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-fluoro-ethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0531]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[3-(2-methoxy-ethoxy)-prop-1-ynyl]-6,-
7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0532]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[3-(2-ethoxy-ethoxy)-prop-1-ynyl]-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0533]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[3-(2-fluoro-ethoxy)-prop-1-ynyl]-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0534]
9-(2,2-Dimethyl-propoxymethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one,
[0535]
9-Cyclohexyloxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one, [0536]
9-Cyclopropylmethoxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one, [0537]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-2-ylmethoxy)-6,7-di-
hydro-pyrimido[6,1-a]isoquinolin-4-one, [0538]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-butyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0539]
9-(4,4-Dimethyl-pentyloxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one, [0540]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pentyl)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one, [0541]
9-(3-Cyclopropyl-propoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0542]
9-Cyclohexylamino-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[-
6,1-a]isoquinolin-4-one, [0543]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4,4-dimethyl-pentyl)-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one, [0544]
9-Cyclopentylmethoxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one, [0545]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-butyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0546]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-phenylamino-propyl)-6,7-dihydro-py-
rimido[6,1-a]isoquinolin-4-one, [0547]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-pentyl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0548]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-butyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0549]
9-(Cyclohexyl-methyl-amino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one, [0550]
9-(Cyclohexylmethyl-amino)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one, [0551]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[(tetrahydro-pyran-4-ylmethyl)-amino]-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0552]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pentyl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one, [0553]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-butyl)-6,7-dihydr-
o-pyrimido[6,1-a]isoquinolin-4-one, [0554]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pentyl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0555]
9-(2,2-Dimethyl-propoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-py-
rimido[6,1-a]isoquinolin-4-one, [0556]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxy)-6,7-di-
hydro-pyrimido[6,1-a]isoquinolin-4-one, [0557]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-4-methyl-pentyl)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one, [0558]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxymethyl)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0559]
2-([1,4]Dioxan-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquino-
lin-4-one, [0560]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(oxetan-3-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0561]
9-(3-Cyclopropyl-propoxy)-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0562]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0563]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0564]
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-tetrahydro-pyran-4-ylethyn-
yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one. [0565]
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0566]
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0567]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0568]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one, [0569]
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0570]
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one, and [0571]
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-butyl)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one. [0572] In another embodiment, the
compound for use is selected from [0573]
9-Methoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0574]
2-(Chroman-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin--
4-one, [0575]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0576]
9-Allyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]is-
oquinolin-4-one, [0577]
2-(2,3-Dihydro-benzofuran-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,1-
-a]isoquinolin-4-one, [0578]
9-Hydroxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0579]
9-Benzyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]i-
soquinolin-4-one, [0580]
9-(Pyridin-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0581]
[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]iso-
quinolin-9-yloxy]-acetonitrile, [0582]
9-Butoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one, [0583]
9-Cyclopropylmethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0584]
9-Phenethyloxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one, [0585]
9-(Pyridin-4-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0586]
9-(Pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0587]
9-(Pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0588]
9-(2-Phenoxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0589]
9-Methoxy-2-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0590]
9-Methoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0591]
9-Methoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]iso-
quinolin-4-one, [0592]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile, [0593]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile, [0594]
9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0595]
9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0596]
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile, [0597]
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzonitrile, [0598]
9-(4-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0599]
9-(3-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0600]
9-(2-Chloro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0601]
9-(4-Fluoro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0602]
9-(2-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0603]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester, [0604]
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester, [0605]
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxymethyl]-benzoic acid methyl ester, [0606]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7--
dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0607]
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetic acid tert-butyl ester, [0608]
2,9-Bis-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one, [0609]
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetic acid, [0610]
9-(3-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0611]
9-(3-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0612]
9-(4-Nitro-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0613]
9-(3-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0614]
9-(4-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0615]
9-(4-Methoxy-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0616]
9-(Naphthalen-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0617]
9-(Naphthalen-1-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0618]
9-(2-Methyl-benzyloxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0619]
9-[2-(2-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one, [0620]
9-[2-(3-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one, [0621]
9-[2-(4-Methoxy-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one, [0622]
9-[2-(2-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one,
9-[2-(3-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one, [0623]
9-[2-(4-Chloro-phenoxy)-ethoxy]-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihy-
dro-pyrimido[6,1-a]isoquinolin-4-one, [0624]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0625]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0626]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0627]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-2-oxo-et-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0628]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-acetamide, [0629]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N,N-dimethyl-acetamide, [0630]
9-(2,2-Dimethoxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyr-
imido[6,1-a]isoquinolin-4-one, [0631]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-2-methyl-propionamide, [0632]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1,1-dimethyl-2-morpholin--
4-yl-2-oxo-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0633]
9-(2-Benzyloxy-ethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0634]
2,9-Bis-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquin-
olin-4-one, [0635]
9-(6-Phenyl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one, [0636]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(tetrahydro-furan-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0637]
9-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridin-2-ylmethoxy]-2-(tetrahydro-furan--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0638]
9-(6-Furan-3-yl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0639]
9-(6-Pyrimidin-5-yl-pyridin-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0640]
9-(1-Cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0641]
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxy]-acetamide, [0642]
N,N-Diethyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-acetamide, [0643]
N,N-Dimethyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyr-
imido[6,1-a]isoquinolin-9-yloxy]-acetamide, [0644]
N-Isopropyl-N-methyl-2-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydr-
o-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetamide, [0645]
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yloxy]-N-phenyl-acetamide, [0646]
9-(1-Propyl-1H-tetrazol-5-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0647]
9-(Oxazol-2-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, [0648]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N,N-diethyl-acetamide, [0649]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N-isopropyl-N-methyl-acetamide,
[0650]
2-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxy]-N-phenyl-acetamide, [0651]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1-propyl-1H-tetrazol-5-yl-
methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0652]
9-(1-Butyl-1H-tetrazol-5-ylmethoxy)-2-(2,3-dihydro-benzo[1,4]dioxin-2-ylm-
ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0653]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-morpholin-4-yl-ethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0654]
[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimi-
do[6,1-a]isoquinolin-9-yloxy]-acetonitrile, [0655]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one, [0656]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-oxo-2-pyrrolidin-1-yl-e-
thoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0657]
9-(1-Cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-(2,3-dihydro-benzo[1,4]dioxin-
-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0658]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(1H-tetrazol-5-ylmethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0659]
9-Allyloxy-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dih-
ydro-pyrimido[6,1-a]isoquinolin-4-one, [0660]
N-Benzyl-2-[2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydr-
o-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetamide, [0661]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-pyrrolidin-1-yl-ethoxy)-
-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0662]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(2-piperidin-1-yl-ethoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0663]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(3-piperidin-1-yl-p-
ropoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0664]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-(3-dimethylamino-propoxy)--
6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0665]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-[2-(1-methy
1-pyrrolidin-2-yl)-ethoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0666]
2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-[3-(4-methyl-pipera-
zin-1-yl)-propoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0667]
5-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
mido[6,1-a]isoquinolin-9-yloxymethyl]-furan-2-carboxylic acid ethyl
ester, [0668]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0669]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0670]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0671]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxazol-2-ylmeth-
oxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0672]
9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0673]
9-(5-Phenyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(tetrahydro-furan-2-ylmethoxy-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0674]
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile, [0675]
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile, [0676]
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-yloxy]-acetonitrile, [0677]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-morpholin-4-y-
l-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0678]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(pyridin-2-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0679]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[2-(1-methyl-pyr-
rolidin-2-yl)-ethoxy]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0680]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-tetrazol-5-y-
lmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0681]
9-Pyridin-3-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1--
a]isoquinolin-4-one, [0682]
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile, [0683]
9-Phenyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoq-
uinolin-4-one, [0684]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-4-yl-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0685]
3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile, [0686]
9-(2-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0687]
9-(3-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0688]
9-(4-Methoxy-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0689]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile, [0690]
3-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzoic acid, [0691]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzoic acid, [0692]
9-(4-Dimethylamino-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0693]
4-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzamide, [0694]
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-benzonitrile, [0695]
9-(1-Methyl-1H-pyrazol-4-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-
-pyrimido[6,1-a]isoquinolin-4-one, [0696]
N,N-Dimethyl-3-[4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyr-
imido[6,1-a]isoquinolin-9-yl]-benzamide, [0697]
9-(6-Methoxy-pyridin-3-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0698]
9-(2,6-Dimethyl-phenyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
mido[6,1-a]isoquinolin-4-one, [0699]
9-(3,5-Dimethyl-isoxazol-4-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihyd-
ro-pyrimido[6,1-a]isoquinolin-4-one, [0700]
9-Naphthalen-2-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one, [0701]
9-Naphthalen-1-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6-
,1-a]isoquinolin-4-one, [0702]
9-Pyrimidin-5-yl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,-
1-a]isoquinolin-4-one, [0703]
9-(5-Chloro-thiophen-2-yl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one, [0704]
2-[4-Oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]i-
soquinolin-9-yl]-pyrrole-1-carboxylic acid tert-butyl ester, [0705]
Trifluoro-methanesulfonic acid
4-oxo-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-4H-pyrimido[6,1-a]isoq-
uinolin-9-yl ester, [0706]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0707]
9-Cyclopropylethynyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrimid-
o[6,1-a]isoquinolin-4-one, [0708]
9-(3,3-Dimethyl-but-1-ynyl)-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro--
pyrimido[6,1-a]isoquinolin-4-one, [0709]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(pyridin-4-ylmet-
hoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0710]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-3-yl-6,7-
-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0711]
2-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzonitrile, [0712]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pheny-
l)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0713]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-indazol-5-yl-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0714]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyrimidin-5-yl-6-
,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0715]
3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-benzamide, [0716]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-dimethylamino-
-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0717]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-3-ylethy-
nyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0718]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methoxy-prop--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0719]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(4-hydroxy-but-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0720]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1,5-dimethyl-1H-
-pyrazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0721]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-[1,2,4-
]oxadiazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0722]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydrox-
y-3-methyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0723]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyridin-4-
-ylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0724]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-prop--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0725]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-methyl-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0726]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0727]
9-Cyclopropylethynyl-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethox-
y)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0728]
9-Cyclopropylethynyl-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethox-
y)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0729]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1-hydroxy-cyclo-
pentylethynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0730]
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pent-4-ynenitrile, [0731]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3,3-dimethyl-bu-
t-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0732]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pyrid-
in-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0733]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one, [0734]
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carboxylic acid
methylamide, [0735]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-furan-3-yl-6,7-d-
ihydro-pyrimido[6,1-a]isoquinolin-4-one, [0736]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1-methyl-1H-pyr-
azol-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0737]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-morpholin-4-ylme-
thyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0738]
[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro-
-4H-pyrimido[6,1-a]isoquinolin-9-ylamino]-acetonitrile, [0739]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carbonitrile, [0740]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[(oxazol-2-ylmet-
hyl)-amino]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0741]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-methyl-[1,2,4-
]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0742]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-ethyl--
[1,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one-
, [0743]
9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(2,3-dihydro-[1,-
4]dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinoli-
n-4-one, [0744]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(5-isopropyl-[1,-
2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0745]
9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethoxy)-2-(2,3-dihydro-[1,4]-
dioxino[2,3-b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin--
4-one, [0746]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-isoxaz-
ol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0747]
9-(3-Chloro-2-methoxy-pyridin-4-yl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyr-
idin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0748]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3,6-dihydro-2H--
pyran-4-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0749]
5-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihyd-
ro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-pyridine-2-carbonitrile,
[0750]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-ethoxy-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0751]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-ethoxy-pyridi-
n-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0752]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(6-morpholin-4-y-
l-pyridin-3-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0753]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-methoxy-pyrim-
idin-5-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0754]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2,3-dimethoxy-p-
henyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0755]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2,5-dimethoxy-p-
henyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0756]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-phe-
nyl-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0757]
3-{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-di-
hydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyloxy}-propionitrile,
[0758]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-
amino-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0759]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-dimethylamino-
-prop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0760]
9-[3-(Benzyl-methyl-amino)-prop-1-ynyl]-2-(2,3-diohydro-[1,4]dioxino[2,3--
b]pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0761]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-[3-(1,1-d-
ioxo-thiomorpholin-4-yl)-prop-1-ynyl]-6,7-dihydro-pyrimido[6,1-a]isoquinol-
in-4-one, [0762]
{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihy-
dro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyl}-urea, [0763]
1-{3-[2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-di-
hydro-4H-pyrimido[6,1-a]isoquinolin-9-yl]-prop-2-ynyl}-imidazolidine-2,4-d-
ione, [0764]
9-(3-Diethylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0765]
9-(3-Amino-3-methyl-but-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-
-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0766]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(tetrahydro-pyra-
n-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0767]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(1H-pyrazol-4-yl-
)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0768]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-but-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0769]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-pent--
1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0770]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-hex-1-
-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0771]
9-(1-Amino-cyclohexylethynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0772]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-5-met-
hyl-hex-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0773]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-ethyl-3-hydro-
xy-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0774]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-3-phe-
nyl-but-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0775]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-hydroxy-4-met-
hyl-pent-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0776]
2-[(R)-1-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9-(oxazol--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0777]
2-[(R)-1-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9-(oxazol--
2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0778]
2-[(S)-1-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9-(-
oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0779]
9-(3-Butylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2--
ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0780]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(2-morpholin-4-y-
l-ethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0781]
9-(3-Benzylamino-prop-1-ynyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-
-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0782]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-phenylamino-p-
rop-1-ynyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0783]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carboxylic acid
(tetrahydro-pyran-4-yl)-amide, [0784]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-4-oxo-6,7-dihydro--
4H-pyrimido[6,1-a]isoquinoline-9-carboxylic acid
(oxetan-3-ylmethyl)-amide, [0785]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-pyrrolidin-1-ylm-
ethyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0786]
9-(tert-Butylamino-methyl)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl-
methoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0787]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-piperidin-1-ylme-
thyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0788]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-oxetan-
-3-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0789]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(3-methyl-oxetan-
-3-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
[0790]
2-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-2-ylmethoxy)-9-(oxetan-3-yloxym-
ethyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, [0791]
9-Cyclopropylethynyl-2-(4-isopropyl-oxetan-2-ylmethoxy)-6,7-dihydro-pyrim-
ido[6,1-a]isoquinolin-4-one, and [0792]
9-Cyclopropylethynyl-2-((R)-4-isopropyl-oxetan-2-ylmethoxy)-6,7-dihydro-p-
yrimido[6,1-a]isoquinolin-4-one.
[0793] In yet another embodiment, the compound for use is selected
from: [0794]
9-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-10-(2,2-
,2-trifluoro-ethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
[0795]
9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methy-
l-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0796]
9-(2,2-difluoro-cyclopropylmethoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10--
methoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0797]
10-(2,2-difluoro-ethoxy)-2-[([1,4]dioxan-2-ylmethyl)-amino]-9-methoxy-1-m-
ethyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0798]
9-(2,2-difluoro-ethoxy)-10-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmeth-
yl)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0799]
10-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-9-(2,2,2-trif-
luoro-ethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0800]
9-(6-cyclopropyl-pyridin-3-yl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-metho-
xy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0801]
2-(2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-9,10-dimethoxy-6,7-d-
ihydro-pyrido[2,1-a]isoquinolin-4-one, [0802]
trifluoro-methanesulfonic acid
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-4-oxo-6,7-dihy-
dro-4H-pyrido[2,1-a]isoquinolin-9-yl ester, [0803]
2-[([1,4]dioxan-2-ylmethyl)-amino]-9-methoxy-1-methyl-10-(2,2,2-trifluoro-
-ethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0804]
10-(2,2-difluoro-ethoxy)-9-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmeth-
yl)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0805]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-9-[6-(2,2,2-trifluo-
ro-ethoxy)-pyridin-3-yl]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
[0806]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(6-fluoro-pyridin-3-yl)-10-met-
hoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0807]
9,10-bis-(2,2-difluoro-cyclopropylmethoxy)-2-((S)-1-[1,4]dioxan-2-ylmetho-
xy)-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0808]
9-(3,3-difluoro-cyclobutylmethoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-m-
ethoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0809]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-9-(2,2,2-trifluoro--
ethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0810]
10-difluoromethoxy-9-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-am-
ino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0811]
10-(2,2-difluoro-ethoxy)-9-methoxy-1-methyl-2-(tetrahydro-pyran-2-ylmethy-
l)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0812]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-9-(6-oxo-1,6-dihydr-
o-pyridin-3-yl)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0813]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-9-(3-methyl-oxetan--
3-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0814]
9-methoxy-1-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-10-(2,2,2-trif-
luoro-ethoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0815]
9-(2,2-difluoro-ethoxy)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-me-
thyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0816]
2-[([1,4]dioxan-2-ylmethyl)-amino]-9,10-dimethoxy-1-methyl-6,7-dihydro-py-
rido[2,1-a]isoquinolin-4-one, [0817]
9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-dihyd-
ro-pyrido[2,1-a]isoquinolin-4-one, [0818]
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-hydroxy-10-methoxy-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one, [0819]
9-difluoromethoxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-6-
,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0820]
9-cyclopropylmethoxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methy-
l-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0821]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(4-ethoxy-3-trifluoromethyl-phenyl)-1-
0-methoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one,
[0822]
9,10-dimethoxy-1-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihyd-
ro-pyrido[2,1-a]isoquinolin-4-one, [0823]
8,9-dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[-
2,1-a]isoquinolin-4-one, [0824]
9,10-dimethoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihyd-
ro-pyrido[2,1-a]isoquinolin-4-one, [0825]
10-difluoromethylsulfanyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-methoxy-1-m-
ethyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0826]
9-methoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-py-
rido[2,1-a]isoquinolin-4-one, [0827]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-9-(4-trifluorometho-
xy-phenyl)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0828]
9-(2,2-difluoro-cyclopropylmethoxy)-1-methyl-2-[(tetrahydro-furan-2-ylmet-
hyl)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0829]
8,9-dimethoxy-1-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one, [0830]
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9,10-dimethoxy-1-methyl-6,7--
dihydro-pyrido[2,1-a]isoquinolin-4-one, [0831]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-methoxy-1,10-dimethyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one, [0832]
8,11-dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one, [0833]
2-[([1,4]dioxan-2-ylmethyl)-amino]-8,11-dimethoxy-6,7-dihydro-pyrido[2,1--
a]isoquinolin-4-one, [0834]
8,11-dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one, [0835]
2-[(R)-1-(2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-2-yl)methoxy]-9,10-dimeth-
oxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0836]
2-[([1,4]dioxan-2-ylmethyl)-amino]-8,9-dimethoxy-1-methyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one, [0837]
10-(2,2-difluoro-ethoxy)-9-methoxy-1-methyl-2-(tetrahydro-pyran-2-ylmetho-
xy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0838]
8,9-dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[-
2,1-a]isoquinolin-4-one, [0839]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-8,9-dimethoxy-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one, [0840]
2-[(S)-1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9,10-dimet-
hoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0841]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(pyridin-2-ylmethoxy)-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one, [0842]
2-[([1,4]dioxan-2-ylmethyl)-amino]-8,9-dimethoxy-6,7-dihydro-pyrido[2,1-a-
]isoquinolin-4-one, [0843]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-4-oxo-6,7-dihydro-4-
H-pyrido[2,1-a]isoquinoline-9-carbonitrile, [0844]
9-methoxy-1-methyl-2-(tetrahydro-pyran-2-ylmethoxy)-10-(2,2,2-trifluoro-e-
thoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0845]
9-(2-cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one, [0846]
9-(2-cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-
-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0847]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-9-(pyridin-2-ylmethoxy)-
-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0848]
9,11-dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one, [0849]
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9,10-dimethoxy-6,7-dihydro-p-
yrido[2,1-a]isoquinolin-4-one, [0850]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9,10-dimethoxy-1-methyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one, [0851] methane sulfonic acid
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-4-oxo-6,7-dihydro-4-
H-pyrido[2,1-a]isoquinolin-9-yl ester, [0852]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-9-pentyl-6,7-dihydro-py-
rido[2,1-a]isoquinolin-4-one, [0853]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(3-methyl-butyl)-6,7-dihydro-
-pyrido[2,1-a]isoquinolin-4-one, [0854]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-10-methoxy-1-methyl-6,7-dihydro-pyrido[-
2,1-a]isoquinolin-4-one, [0855]
2-([1,4]dioxan-2-ylmethoxy)-9,10-dimethoxy-6,7-dihydro-pyrido[2,1-a]isoqu-
inolin-4-one, [0856]
8,11-dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one, [0857]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(5-ethyl-[1,2,4]oxadiazol-3-ylmethoxy-
)-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0858]
2-[([1,4]dioxan-2-ylmethyl)-amino]-9,11-dimethoxy-6,7-dihydro-pyrido[2,1--
a]isoquinolin-4-one, [0859]
8,9-dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]i-
soquinolin-4-one, [0860]
2-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one, [0861] 9-methoxy-1-methy
1-10-(pyridin-2-ylmethoxy)-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one, [0862]
9-(3,5-dimethyl-isoxazol-4-yl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-
-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0863]
9-benzyloxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one, [0864]
9,11-dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-4-one, [0865]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-hydroxy-10-methoxy-1-methyl-6,7-dihyd-
ro-pyrido[2,1-a]isoquinolin-4-one, [0866]
8,9-dimethoxy-1-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one, [0867]
9-benzyloxy-1-cyclopropyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one, [0868]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-8,11-dimethoxy-6,7-dihydro-pyrido[2,1-a-
]isoquinolin-4-one, [0869]
9-(3,6-dihydro-2H-pyran-4-yl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl--
6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0870]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-9-(oxazol-2-ylmethoxy)--
6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0871]
9,11-dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one, [0872]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(tetrahydro-pyran-4-yl)-6,7--
dihydro-pyrido[2,1-a]isoquinolin-4-one, [0873]
9-benzyloxy-2-([1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-6,7-dihydro-pyrid-
o[2,1-a]isoquinolin-4-one, [0874]
[2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-4-oxo-6,7-dihydro-4H-pyrido[2-
,1-a]isoquinolin-9-yloxy]-acetonitrile, [0875]
9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-6,-
7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0876]
9,10-dimethoxy-1-methyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyri-
do[2,1-a]isoquinolin-4-one, [0877]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(3-methyl-but-1-ynyl)-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one, [0878]
9-(5,6-dihydro-[1,4]dioxin-2-yl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-meth-
yl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0879]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-ethoxy-1-methyl-6,7-dihydro-pyrido[2,-
1-a]isoquinolin-4-one, [0880]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(1-methyl-1H-pyrazol-4-yl)-6-
,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0881]
[2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-4-oxo-6,7-dihydro-4H-pyrido[2,-
1-a]isoquinolin-9-yloxy]-acetonitrile, [0882]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(1-propyl-1H-tetrazol-5-ylme-
thoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0883]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-8,9-dimethoxy-1-methyl-6,7-dihydro-pyri-
do[2,1-a]isoquinolin-4-one, [0884]
8,11-dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one, [0885]
9-[1,4]dioxan-2-yl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-dihydro-
-pyrido[2,1-a]isoquinolin-4-one, [0886]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-methoxy-1-methyl-6,7-dihydro-pyrido[2-
,1-a]isoquinolin-4-one, [0887]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-8-hydroxy-9-methoxy-1-methyl-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one, [0888]
9-(1-cyclopropyl-1H-tetrazol-5-ylmethoxy)-2-((S)-1-[1,4]dioxan-2-ylmethox-
y)-1-methyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0889]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-4-oxo-9-(2,2,2-trifluoro-ethox-
y)-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-10-carbonitrile, [0890]
2,9-bis-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-dihydro-pyrido[2,1-a-
]isoquinolin-4-one, [0891]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9,11-dimethoxy-6,7-dihydro-pyrido[2,1-a-
]isoquinolin-4-one, [0892]
8,9-dimethoxy-1-methyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrid-
o[2,1-a]isoquinolin-4-one, [0893]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-9-(3-methyl-oxetan-3-ylmethoxy-
)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0894]
9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one, [0895]
9,10-dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one, [0896]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(pyridin-2-ylmethoxy)-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one, [0897]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(1H-tetrazol-5ylmethoxy)-6,7--
dihydro-pyrido[2,1-a]isoquinolin-4-one, [0898]
2-cyclohexylmethoxy-9,10-dimethoxy-1-methyl-6,7-dihydro-pyrido[2,1-a]isoq-
uinolin-4-one, [0899]
9,10-dimethoxy-1-methyl-2-[(tetrahydro-pyran-3-ylmethyl)-amino]-6,7-dihyd-
ro-pyrido[2,1-a]isoquinolin-4-one, [0900]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(1-methyl-1H-pyrazol-4-yl)-6,-
7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0901]
9,10-dimethoxy-1-methyl-2-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyri-
do[2,1-a]isoquinolin-4-one, [0902]
9-cyclopropylmethoxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1,7,7-trimethyl-6,-
7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0903]
8,9-dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]i-
soquinolin-4-one, [0904]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(3-methoxy-but-1-ynyl)-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one, [0905]
8,9-dimethoxy-1-methyl-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrid-
o[2,1-a]isoquinolin-4-one, [0906]
9-benzyloxy-1-cyclopropyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-p-
yrido[2,1-a]isoquinolin-4-one, [0907]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(3-methyl-but-1-ynyl)-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one, [0908]
trifluoro-methanesulfonic acid
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-4-oxo-6,7-dihydro-4H-pyrido[2,1-
-a]isoquinolin-9-yl ester, [0909]
9-(2-cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one, [0910]
9-cyclopropylmethoxy-2-([1,4]dioxan-2-ylmethoxy)-1-methyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one, [0911]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(3-methyl-butyl)-6,7-dihydro--
pyrido[2,1-a]isoquinolin-4-one, [0912]
9,11-dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,1-a]-
isoquinolin-4-one, [0913]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-hydroxy-1,7,7-trimethyl-6,7-dihydro-p-
yrido[2,1-a]isoquinolin-4-one, [0914]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-methoxy-1-methyl-4-oxo-6,7-dihydro-4H-
-pyrido[2,1-a]isoquinoline-10-carbonitrile, [0915]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-pentyl-6,7-dihydro-pyrido[2,1-
-a]isoquinolin-4-one, [0916]
1-cyclopropyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-pentyl-6,7-dihydro-pyri-
do[2,1-a]isoquinolin-4-one, [0917]
9-benzyloxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one, [0918]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-(3-methoxy-butyl)-6,7-dihydro-
-pyrido[2,1-a]isoquinolin-4-one, [0919]
1-cyclopropyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-methyl-butyl)-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one,
[0920]
1-cyclopropyl-9-(2-cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmet-
hoxy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0921]
trifluoro-methanesulfonic acid
1-cyclopropyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyri-
do[2,1-a]isoquinolin-9-yl ester, [0922] trifluoro-methanesulfonic
acid
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-4-oxo-6,7-dihydro-4H-pyrido-
[2,1-a]isoquinolin-9-yl ester, [0923]
1-cyclopropyl-9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7--
dihydro-pyrido[2,1-a]isoquinolin-4-one, [0924]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-9-(3-methyl-butyl)-6,7-dihy-
dro-pyrido[2,1-a]isoquinolin-4-one, [0925]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-hydroxy-8-methoxy-1-methyl-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one, [0926]
9-(2-cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-6,7-
-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0927]
1-cyclopropyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-(3-methyl-but-1-ynyl)-6-
,7-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0928]
2-([1,4]dioxan-2-ylmethoxy)-9-(2-methoxy-ethoxy)-1-methyl-6,7-dihydro-pyr-
ido[2,1-a]isoquinolin-4-one, [0929]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-9-(3-methyl-but-1-ynyl)-6,7-
-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0930]
9-cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-isopropyl-6,7-di-
hydro-pyrido[2,1-a]isoquinolin-4-one, [0931]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-hydroxy-1-methyl-6,7-dihydro-pyrido[2-
,1-a]isoquinolin-4-one, [0932] trifluoro-methanesulfonic acid
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-methyl-4-oxo-6,7-dihydro-4H-pyrido[2,-
1-a]isoquinolin-9-yl ester, [0933]
2-((S)-1-[1,4]dioxan-2-ylmethoxy)-1-ethyl-9-hydroxy-6,7-dihydro-pyrido[2,-
1-a]isoquinolin-4-one, [0934]
9-methoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,1--
a]isoquinolin-4-one, [0935]
10-hydroxy-9-methoxy-1-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-
-dihydro-pyrido[2,1-a]isoquinolin-4-one, [0936]
2-[([1,4]dioxan-2-ylmethyl)-amino]-10-hydroxy-9-methoxy-1-methyl-6,7-dihy-
dro-pyrido[2,1-a]isoquinolin-4-one, [0937]
10-hydroxy-9-methoxy-1-methyl-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydr-
o-pyrido[2,1-a]isoquinolin-4-one, and [0938]
10-benzyloxy-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-9-methoxy-1-methyl-6,7-dih-
ydro-pyrido[2,1-a]isoquinolin-4-one.
[0939] In a further embodiment, the compound for use is selected
from [0940]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9,10-dimethoxy-1-methyl-6,7-dihy-
drobenzo[a]quinolizin-2-one, [0941]
9,10-dimethoxy-1-methyl-4-(tetrahydrofuran-2-ylmethylamino)-6,7-dihydrobe-
nzo[a]quinolizin-2-one, [0942]
1-ethyl-9-hydroxy-4-(tetrahydrofuran-2-ylmethylamino)-6,7-dihydrobenzo[a]-
quinolizin-2-one, [0943]
9,10-Dimethoxy-4-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido-
[2,1-a]isoquinolin-2-one, [0944]
4-[([1,4]Dioxan-2-ylmethyl)-amino]-9,10-dimethoxy-6,7-dihydro-pyrido[2,1--
a]isoquinolin-2-one, [0945]
4-[[(2R)-1,4-dioxan-2-yl]methylamino]-9,10-dimethoxy-1-methyl-6,7-dihydro-
benzo[a]quinolizin-2-one, [0946]
9-(2,2-Difluoro-cyclopropylmethoxy)-1-methyl-4-[(tetrahydro-furan-2-ylmet-
hyl)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-2-one, [0947]
1-methyl-4-(tetrahydrofuran-2-ylmethylamino)-9-(2,2,2-trifluoroethoxy)-6,-
7-dihydrobenzo[a]quinolizin-2-one, [0948]
-Methyl-4-[(tetrahydro-furan-2-ylmethyl)-amino]-9-(tetrahydro-furan-2-ylo-
xy)-6,7-dihydro-pyrido[2,1-a]isoquinolin-2-one, [0949]
8,9-dimethoxy-1-methyl-4-(tetrahydrofuran-2-ylmethylamino)-6,7-dihydroben-
zo[a]quinolizin-2-one, [0950]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-8,9-dimethoxy-1-methyl-6,7-dihydrobenzo-
[a]quinolizin-2-one, [0951]
9-(2,2-difluoroethoxy)-1-methyl-4-(tetrahydropyran-2-ylmethylamino)-6,7-d-
ihydrobenzo[a]quinolizin-2-one, [0952]
1-methyl-4-(tetrahydropyran-2-ylmethylamino)-9-(2,2,2-trifluoroethoxy)-6,-
7-dihydrobenzo[a]quinolizin-2-one, [0953]
8,9-dimethoxy-1-methyl-4-(tetrahydropyran-2-ylmethylamino)-6,7-dihydroben-
zo[a]quinolizin-2-one, [0954]
4-(1,4-dioxan-2-ylmethylamino)-8,9-dimethoxy-1-methyl-6,7-dihydrobenzo[a]-
quinolizin-2-one, [0955]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2,2,2-trifluoroethoxy)-6,7--
dihydrobenzo[a]quinolizin-2-one, [0956]
4-(1,4-dioxan-2-ylmethylamino)-8,9-dimethoxy-6,7-dihydrobenzo[a]quinolizi-
n-2-one, [0957]
8,9-dimethoxy-4-(tetrahydrofuran-2-ylmethylamino)-6,7-dihydrobenzo[a]quin-
olizin-2-one, [0958]
4-(1,4-dioxan-2-ylmethylamino)-9-hydroxy-8-methoxy-6,7-dihydrobenzo[a]qui-
nolizin-2-one, [0959]
4-(1,4-dioxan-2-ylmethylamino)-8-hydroxy-9-methoxy-6,7-dihydrobenzo[a]qui-
nolizin-2-one, [0960]
9-(2,2-Difluoro-ethoxy)-4-[([1,4]dioxan-2-ylmethyl)-amino]-8-methoxy-1-me-
thyl-6,7-dihydro-pyrido[2,1-a]isoquinolin-2-one, [0961]
9-(2,2-Difluoro-ethoxy)-8-methoxy-1-methyl-4-[(tetrahydro-furan-2-ylmethy-
l)-amino]-6,7-dihydro-pyrido[2,1-a]isoquinolin-2-one, [0962]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]quino-
lizine-9-carbonitrile, [0963]
9-(2,2-difluoroethoxy)-1-ethyl-4-(tetrahydrofuran-2-ylmethylamino)-6,7-di-
hydrobenzo[a]quinolizin-2-one, [0964]
1-ethyl-4-(tetrahydrofuran-2-ylmethylamino)-9-(2,2,2-trifluoroethoxy)-6,7-
-dihydrobenzo[a]quinolizin-2-one, [0965]
8,9-dimethoxy-1-methyl-4-(tetrahydrofuran-2-ylmethoxy)-6,7-dihydrobenzo[a-
]quinolizin-2-one, [0966]
8,9-dimethoxy-1-methyl-4-(tetrahydropyran-2-ylmethoxy)-6,7-dihydrobenzo[a-
]quinolizin-2-one, [0967]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(tetrahydropyran-4-ylmethoxy-
)-6,7-dihydrobenzo[a]quinolizin-2-one, [0968]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2-pyridylmethoxy)-6,7-dihyd-
robenzo[a]quinolizin-2-one, [0969]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[[3-(trifluoromethoxy)phenyl-
]methoxy]-6,7-dihydrobenzo[a]quinolizin-2-one, [0970]
9-benzyloxy-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrobenzo[a-
]quinolizin-2-one, [0971]
9-benzyloxy-4-[[(2R)-1,4-dioxan-2-yl]methylamino]-1-methyl-6,7-dihydroben-
zo[a]quinolizin-2-one, [0972]
9-(2,2-difluoroethoxy)-4-[[(2R)-1,4-dioxan-2-yl]methylamino]-1-methyl-6,7-
-dihydrobenzo[a]quinolizin-2-one, [0973]
4-[[(2R)-1,4-dioxan-2-yl]methylamino]-1-methyl-9-(2,2,2-trifluoroethoxy)--
6,7-dihydrobenzo[a]quinolizin-2-one, [0974]
[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]quin-
olizin-9-yl]trifluoromethane sulfonate, [0975]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[(1-methylpyrazol-4-yl)metho-
xy]-6,7-dihydrobenzo[a]quinolizin-2-one, [0976]
9-(3,6-dihydro-2H-pyran-4-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl--
6,7-dihydrobenzo[a]quinolizin-2-one, [0977]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(1-ethylpyrazol-4-yl)-1-methyl-6,7-di-
hydrobenzo[a]quinolizin-2-one, [0978]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-tetrahydropyran-4-yl-6,7-dih-
ydrobenzo[a]quinolizin-2-one, [0979]
1-methyl-4-[[(2S)-tetrahydrofuran-2-yl]methylamino]-9-(2,2,2-trifluoroeth-
oxy)-6,7-dihydrobenzo[a]quinolizin-2-one, [0980]
1-methyl-9-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]-4-(tetrahydrofuran-2--
ylmethoxy)-6,7-dihydrobenzo[a]quinolizin-2-one, [0981]
1-methyl-9-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]-4-(tetrahydropyran-2--
ylmethoxy)-6,7-dihydrobenzo[a]quinolizin-2-one, [0982]
1-methyl-9-(2-pyridylmethoxy)-4-(tetrahydrofuran-2-ylmethoxy)-6,7-dihydro-
benzo[a]quinolizin-2-one, [0983]
1-methyl-9-(2-pyridylmethoxy)-4-(tetrahydropyran-2-ylmethoxy)-6,7-dihydro-
benzo[a]quinolizin-2-one, [0984]
1-methyl-4-(tetrahydrofuran-2-ylmethoxy)-9-(tetrahydropyran-3-ylmethoxy)--
6,7-dihydrobenzo[a]quinolizin-2-one, [0985]
1-methyl-4-(tetrahydropyran-2-ylmethoxy)-9-(tetrahydropyran-3-ylmethoxy)--
6,7-dihydrobenzo[a]quinolizin-2-one, [0986]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(tetrahydropyran-3-ylmethoxy-
)-6,7-dihydrobenzo[a]quinolizin-2-one, [0987]
1-methyl-9-[(6-methyl-3-pyridyl)methoxy]-4-(tetrahydrofuran-2-ylmethoxy)--
6,7-dihydrobenzo[a]quinolizin-2-one, [0988]
1-methyl-9-[(6-methyl-3-pyridyl)methoxy]-4-(tetrahydropyran-2-ylmethoxy)--
6,7-dihydrobenzo[a]quinolizin-2-one, [0989]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[(6-methyl-3-pyridyl)methoxy-
]-6,7-dihydrobenzo[a]quinolizin-2-one, [0990]
9-(2-dimethylaminoethyloxy)-1-methyl-4-(tetrahydrofuran-2-ylmethoxy)-6,7--
dihydrobenzo[a]quinolizin-2-one, [0991]
9-(2-dimethylaminoethyloxy)-1-methyl-4-(tetrahydropyran-2-ylmethoxy)-6,7--
dihydrobenzo[a]quinolizin-2-one, [0992]
9-(2-dimethylaminoethyloxy)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,-
7-dihydrobenzo[a]quinolizin-2-one, [0993]
[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]quin-
olizin-9-yl]methanesulfonate, [0994]
1-methyl-9-(2-pyridylmethoxy)-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]-6,7--
dihydrobenzo[a]quinolizin-2-one, [0995]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[(3-methyl-1,2,4-oxadiazol-5-
-yl)methoxy]-6,7-dihydrobenzo[a]quinolizin-2-one, [0996]
9-(difluoromethoxy)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydr-
obenzo[a]quinolizin-2-one, [0997] tert-butyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperazine-1-carboxylate, [0998]
9-(2,2-difluoroethoxy)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dih-
ydrobenzo[a]quinolizin-2-one, [0999]
4,9-bis[[2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrobenzo[a]quinoli-
zin-2-one, [1000]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-morpholino-6,7-dihydrobenzo[-
a]quinolizin-2-one, [1001]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-phenylsulfanyl-6,7-dihydrobe-
nzo[a]quinolizin-2-one, [1002]
9-(4,4-difluoro-1-piperidyl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6-
,7-dihydrobenzo[a]quinolizin-2-one, [1003]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-piperazin-1-yl-6,7-dihydrobe-
nzo[a]quinolizin-2-one, [1004] 9-(benzene
sulfonyl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrobenzo[a]q-
uinolizin-2-one, [1005]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(4-methylsulfonylpiperazin-1-
-yl)-6,7-dihydrobenzo[a]quinolizin-2-one, [1006]
9-[4-(cyclopropanecarbonyl)piperazin-1-yl]-4-[[(2S)-1,4-dioxan-2-yl]metho-
xy]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one, [1007]
N-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]cyclopropanecarboxamide, [1008] tert-butyl
3-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]azetidine-1-carboxylate, [1009]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[2-(trifluoromethoxy)ethoxy]-
-6,7-dihydrobenzo[a]quinolizin-2-one, [1010]
N-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-N-methyl-cyclopropanecarboxamide, [1011] tert-butyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylate, [1012]
tert-butyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-1-carboxylate, [1013] methyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylate, [1014] ethyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylate, [1015]
isopropyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylate, [1016]
2,2,2-trifluoroethyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylate, [1017] methyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-1-carboxylate, [1018] ethyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-1-carboxylate, [1019] isopropyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-1-carboxylate, [1020] 2,2,2-trifluoroethyl
4-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-1-carboxylate, [1021]
N-cyclopropyl-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydr-
obenzo[a]quinolizine-9-carboxamide, [1022]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-hydroxy-1-methyl-6,7-dihydrobenzo[a]q-
uinolizin-2-one, [1023]
9-(3,3-difluoroazetidin-1-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl--
6,7-dihydrobenzo[a]quinolizin-2-one, [1024]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(6-oxa-2-azaspiro[3.3]heptan-
-2-yl)-6,7-dihydrobenzo[a]quinolizin-2-one, [1025]
N-cyclopropyl-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-N,
1-dimethyl-2-oxo-6,7-dihydrobenzo[a]quinolizine-9-carboxamide,
[1026]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-methoxy-1-methyl-6,7-dihydrobenzo[a]q-
uinolizin-2-one, [1027]
4-(1,4-dioxan-2-ylmethoxy)-1-methyl-9-(2,2,2-trifluoroethoxy)-6,7-dihydro-
benzo[a]quinolizin-2-one, [1028]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(3-fluoroazetidin-1-yl)-1-methyl-6,7--
dihydrobenzo[a]quinolizin-2-one, [1029]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-[3-(1-hydroxy-1-methyl-ethyl)azetidin-
-1-yl]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one, [1030]
9-(azetidin-1-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrob-
enzo[a]quinolizin-2-one, [1031]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(3-methylsulfonylazetidin-1--
yl)-6,7-dihydrobenzo[a]quinolizin-2-one, [1032]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(3-pyrazol-1-ylazetidin-1-yl-
)-6,7-dihydrobenzo[a]quinolizin-2-one, [1033]
9-(3,3-dimethylazetidin-1-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl--
6,7-dihydrobenzo[a]quinolizin-2-one, [1034] methyl
1-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]azetidine-3-carboxylate, [1035]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(3-pyridyl)-6,7-dihydrobenzo-
[a]quinolizin-2-one, [1036]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(3-fluorophenyl)-1-methyl-6,7-dihydro-
benzo[a]quinolizin-2-one, [1037]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(4-pyridyl)-6,7-dihydrobenzo-
[a]quinolizin-2-one, [1038]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2-pyridyl)-6,7-dihydrobenzo-
[a]quinolizin-2-one, [1039]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(3-methyl-2-pyridyl)-6,7-dih-
ydrobenzo[a]quinolizin-2-one, [1040]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(4-methyl-2-pyridyl)-6,7-dih-
ydrobenzo[a]quinolizin-2-one, [1041] tert-butyl
3-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]azetidine-1-carboxylate, [1042]
3-deuterio-9-(1-deuterio-2,2-difluoro-vinyloxy)-4-[[(2S)-1,4-dioxan-2-yl]-
methoxy]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one, [1043]
9-(1,1-dideuterio-2,2,2-trifluoro-ethoxy)-4-[[(2S)-1,4-dioxan-2-yl]methox-
y]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one, [1044]
9-benzyloxy-1-methyl-4-(oxetan-2-ylmethoxy)-6,7-dihydrobenzo[a]quinolizin-
-2-one, [1045]
9-benzyloxy-1-methyl-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]-6,7-dihydrobe-
nzo[a]quinolizin-2-one, [1046]
9-benzyloxy-1-methyl-4-(tetrahydropyran-2-ylmethoxy)-6,7-dihydrobenzo[a]q-
uinolizin-2-one, [1047]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(3-methoxyazetidin-1-yl)-1-methyl-6,7-
-dihydrobenzo[a]quinolizin-2-one, [1048]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(4-methoxy-1-piperidyl)-1-methyl-6,7--
dihydrobenzo[a]quinolizin-2-one, [1049]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[4-(piperidine-1-carbonyl)-1-
-piperidyl]-6,7-dihydrobenzo[a]quinolizin-2-one, [1050]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(4-phenyl-1-piperidyl)-6,7-d-
ihydrobenzo[a]quinolizin-2-one, [1051] methyl
1-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-4-carboxylate, [1052]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-[4-(ethoxymethyl)-1-piperidyl]-1-meth-
yl-6,7-dihydrobenzo[a]quinolizin-2-one, [1053]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(1-piperidyl)-6,7-dihydroben-
zo[a]quinolizin-2-one, [1054]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(3-methyl-1-piperidyl)-6,7-d-
ihydrobenzo[a]quinolizin-2-one, [1055]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-[4-(4-fluorophenyl)-1-piperidyl]-1-me-
thyl-6,7-dihydrobenzo[a]quinolizin-2-one, [1056]
9-[1-(cyclopropanecarbonyl)azetidin-3-yl]oxy-4-[[(2S)-1,4-dioxan-2-yl]met-
hoxy]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one, [1057]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[1-(2,2,2-trifluoroacetyl)az-
etidin-3-yl]oxy-6,7-dihydrobenzo[a]quinolizin-2-one, [1058] ethyl
3-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]azetidine-1-carboxylate, [1059]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[4-(3-pyridyloxy)-1-piperidy-
l]-6,7-dihydrobenzo[a]quinolizin-2-one, [1060]
1-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]piperidine-4-carbonitrile, [1061]
9-(3,3-difluoro-1-piperidyl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6-
,7-dihydrobenzo[a]quinolizin-2-one, [1062]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-isopropyl-1-methyl-6,7-dihydrobenzo[a-
]quinolizin-2-one, [1063]
3-deuterio-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2,2,2-trifluoroe-
thoxy)-6,7-dihydrobenzo[a]quinolizin-2-one, [1064]
3-deuterio-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(1,1,2,2-tetradeu-
terio-2-fluoro-ethoxy)-6,7-dihydrobenzo[a]quinolizin-2-one, [1065]
tert-butyl
3-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]pyrrolidine-1-carboxylate, [1066] tert-butyl
4-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]piperidine-1-carboxylate, [1067]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[methyl(3,3,3-trifluoropropy-
l)amino]-6,7-dihydrobenzo[a]quinolizin-2-one, [1068]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-pyrrolidin-1-yl-6,7-dihydrob-
enzo[a]quinolizin-2-one,
[1069]
9-(3,3-difluoropyrrolidin-1-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]--
1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one, [1070]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[3-(trifluoromethyl)azetidin-
-1-yl]-6,7-dihydrobenzo[a]quinolizin-2-one, [1071]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[4-(trifluoromethyl)-3,6-dih-
ydro-2H-pyridin-1-yl]-6,7-dihydrobenzo[a]quinolizin-2-one, [1072]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[(2R)-2-methylpyrrolidin-1-y-
l]-6,7-dihydrobenzo[a]quinolizin-2-one, [1073]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-9-(3-fluoro-1-piperidyl)-1-methyl-6,7-d-
ihydrobenzo[a]quinolizin-2-one, [1074]
9-carbazol-9-yl-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydroben-
zo[a]quinolizin-2-one, [1075]
9-(3,5-dimethyl-1-piperidyl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6-
,7-dihydrobenzo[a]quinolizin-2-one, [1076]
9-(3,3-dimethylpyrrolidin-1-yl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methy-
l-6,7-dihydrobenzo[a]quinolizin-2-one, [1077]
9-(4,4-dimethyl-1-piperidyl)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6-
,7-dihydrobenzo[a]quinolizin-2-one, [1078]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[4-(trifluoromethyl)-1-piper-
idyl]-6,7-dihydrobenzo[a]quinolizin-2-one, [1079]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(4-methyl-1-piperidyl)-6,7-d-
ihydrobenzo[a]quinolizin-2-one, [1080]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2,2,2-trifluoroethylamino)--
6,7-dihydrobenzo[a]quinolizin-2-one, [1081]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2-methyl-1-piperidyl)-6,7-d-
ihydrobenzo[a]quinolizin-2-one, [1082]
9-[1-(cyclopropanecarbonyl)pyrrolidin-3-yl]oxy-4-[[(2S)-1,4-dioxan-2-yl]m-
ethoxy]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one, [1083] ethyl
3-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]pyrrolidine-1-carboxylate, [1084]
9-[1-(cyclopropanecarbonyl)azetidin-3-yl]-4-[[(2S)-1,4-dioxan-2-yl]methox-
y]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one, [1085] ethyl
3-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]azetidine-1-carboxylate, [1086]
3-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-N,N-dimethyl-azetidine-1-carboxamide, [1087]
3-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-N-isopropyl-azetidine-1-carboxamide, [1088]
3-[[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]q-
uinolizin-9-yl]oxy]-N,N-dimethyl-azetidine-1-carboxamide, [1089]
3-[4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-2-oxo-6,7-dihydrobenzo[a]qu-
inolizin-9-yl]-N-isopropyl-azetidine-1-carboxamide, [1090]
9-benzyloxy-4-[(4,4-dimethyloxetan-2-yl)methoxy]-1-methyl-6,7-dihydrobenz-
o[a]quinolizin-2-one, [1091]
9-benzyloxy-1-methyl-4-[(2-methyltetrahydrofuran-2-yl)methoxy]-6,7-dihydr-
obenzo[a]quinolizin-2-one, [1092]
9-benzyloxy-4-[(5,5-dimethyltetrahydrofuran-2-yl)methoxy]-1-methyl-6,7-di-
hydrobenzo[a]quinolizin-2-one, [1093]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2,2,3,3,3-pentafluoropropox-
y)-6,7-dihydrobenzo[a]quinolizin-2-one, [1094]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrobenzo[a]quinolizin--
2-one, [1095]
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2-oxopyrrolidin-1-yl)-6,7-d-
ihydrobenzo[a]quinolizin-2-one, and [1096]
3-deuterio-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(1,1,2,2-tetradeu-
terio-2-fluoro-ethoxy)-6,7-dihydrobenzo[a]quinolizin-2-one.
[1097] In one embodiment, the compound for use is
9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one.
[1098] In another embodiment, the compound for use is
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2,2,2-trifluoroethoxy)-6,7--
dihydrobenzo[a]quinolizin-2-one.
[1099] In one embodiment a compound of the invention is not an
isotopic variant.
[1100] In one aspect a compound of the invention according to any
one of the embodiments herein described is present as the free
base.
[1101] In one aspect a compound of the invention according to any
one of the embodiments herein described is a pharmaceutically
acceptable salt.
[1102] In one aspect a compound of the invention according to any
one of the embodiments herein described is a solvate of the
compound.
[1103] In one aspect a compound of the invention according to any
one of the embodiments herein described is a solvate of a
pharmaceutically acceptable salt of a compound.
[1104] While specified groups for each embodiment have generally
been listed above separately, a compound of the invention includes
one in which several or each embodiment in the above Formula, as
well as other formulae presented herein, is selected from one or
more of particular members or groups designated respectively, for
each variable. Therefore, this invention is intended to include all
combinations of such embodiments within its scope.
[1105] While specified groups for each embodiment have generally
been listed above separately, a compound of the invention may be
one for which one or more variables (for example, R groups) is
selected from one or more embodiments according to any of the
Formula(e) listed above. Therefore, the present invention is
intended to include all combinations of variables from any of the
disclosed embodiments within its scope.
[1106] Alternatively, the exclusion of one or more of the specified
variables from a group or an embodiment, or combinations thereof is
also contemplated by the present invention.
[1107] In certain aspects, the present invention provides prodrugs
and derivatives of the compounds according to the formulae above.
Prodrugs are derivatives of the compounds of the invention, which
have metabolically cleavable groups and become by solvolysis or
under physiological conditions the compounds of the invention,
which are pharmaceutically active, in vivo. Such examples include,
but are not limited to, choline ester derivatives and the like,
N-alkylmorpholine esters and the like.
[1108] Other derivatives of the compounds of this invention have
activity in both their acid and acid derivative forms, but the acid
sensitive form often offers advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism
(Bundgard, H, 1985). Prodrugs include acid derivatives well known
to practitioners of the art, such as, for example, esters prepared
by reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides and anhydrides derived
from acidic groups pendant on the compounds of this invention are
preferred prodrugs. In some cases it is desirable to prepare double
ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the
C.sub.1 to C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, aryl,
C.sub.7-C.sub.12 substituted aryl, and C.sub.7-C.sub.12 arylalkyl
esters of the compounds of the invention.
Pharmaceutical Compositions
[1109] When employed as a pharmaceutical, a compound of the
invention is typically administered in the form of a pharmaceutical
composition. Such compositions can be prepared in a manner well
known in the pharmaceutical art and comprise at least one active
compound of the invention according to Formula I. Generally, a
compound of the invention is administered in a pharmaceutically
effective amount. The amount of compound of the invention actually
administered will typically be determined by a physician, in the
light of the relevant circumstances, including the condition to be
treated, the chosen route of administration, the actual compound of
the invention administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[1110] The pharmaceutical compositions of this invention can be
administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intra-articular, intravenous,
intramuscular, and intranasal. Depending on the intended route of
delivery, a compound of the invention is preferably formulated as
either injectable or oral compositions or as salves, as lotions or
as patches all for transdermal administration.
[1111] The compositions for oral administration can take the form
of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term `unit dosage forms`
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient, vehicle or carrier. Typical unit dosage
forms include prefilled, premeasured ampules or syringes of the
liquid compositions or pills, tablets, capsules or the like in the
case of solid compositions. In such compositions, the compound of
the invention according to Formula I is usually a minor component
(from about 0.1 to about 50% by weight or preferably from about 1
to about 40% by weight) with the remainder being various vehicles
or carriers and processing aids helpful for forming the desired
dosing form.
[1112] Liquid forms suitable for oral administration may include a
suitable aqueous or non-aqueous vehicle with buffers, suspending
and dispensing agents, colorants, flavors and the like. Solid forms
may include, for example, any of the following ingredients, or
compound of the inventions of a similar nature: a binder such as
microcrystalline cellulose, gum tragacanth or gelatin; an excipient
such as starch or lactose, a disintegrating agent such as alginic
acid, Primogel, or corn starch; a lubricant such as magnesium
stearate; a glidant such as colloidal silicon dioxide; a sweetening
agent such as sucrose or saccharin; or a flavoring agent such as
peppermint or orange flavoring.
[1113] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
carriers known in the art. As before, the active compound of the
invention according to Formula I in such compositions is typically
a minor component, often being from about 0.05 to 10% by weight
with the remainder being the injectable carrier and the like.
[1114] Transdermal compositions are typically formulated as a
topical ointment or cream containing the active ingredient(s),
generally in an amount ranging from about 0.01 to about 20% by
weight, preferably from about 0.1 to about 20% by weight,
preferably from about 0.1 to about 10% by weight, and more
preferably from about 0.5 to about 15% by weight. When formulated
as an ointment, the active ingredients will typically be combined
with either a paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream
with, for example an oil-in-water cream base. Such transdermal
formulations are well-known in the art and generally include
additional ingredients to enhance the dermal penetration of
stability of the active ingredients or the formulation. All such
known transdermal formulations and ingredients are included within
the scope of this invention.
[1115] A compound of the invention can also be administered by a
transdermal device. Accordingly, transdermal administration can be
accomplished using a patch either of the reservoir or porous
membrane type, or of a solid matrix variety.
[1116] The above-described components for orally administrable,
injectable or topically administrable compositions are merely
representative. Other materials as well as processing techniques
and the like are set forth in Part 8 of Remington's Pharmaceutical
Sciences, 17.sup.th edition, 1985, Mack Publishing Company, Easton,
Pa., which is incorporated herein by reference.
[1117] A compound of the invention can also be administered in
sustained release forms or from sustained release drug delivery
systems. A description of representative sustained release
materials can be found in Remington's Pharmaceutical Sciences.
[1118] The following formulation examples illustrate representative
pharmaceutical compositions that may be prepared in accordance with
this invention. The present invention, however, is not limited to
the following pharmaceutical compositions.
Formulation 1--Tablets
[1119] A compound of the invention according to Formula I may be
admixed as a dry powder with a dry gelatin binder in an approximate
1:2 weight ratio. A minor amount of magnesium stearate may be added
as a lubricant. The mixture may be formed into 240-270 mg tablets
(80-90 mg of active compound of the invention according to Formula
I per tablet) in a tablet press.
Formulation 2--Capsules
[1120] A compound of the invention according to Formula I may be
admixed as a dry powder with a starch diluent in an approximate 1:1
weight ratio. The mixture may be filled into 250 mg capsules (125
mg of active compound of the invention according to Formula I per
capsule).
Formulation 3--Liquid
[1121] A compound of the invention according to Formula I (125 mg),
may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the
resultant mixture may be blended, passed through a No. 10 mesh U.S.
sieve, and then mixed with a previously made solution of
microcrystalline cellulose and sodium carboxymethyl cellulose
(11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color
may be diluted with water and added with stirring. Sufficient water
may then be added with stirring. Further sufficient water may be
then added to produce a total volume of 5 mL.
Formulation 4--Tablets
[1122] A compound of the invention according to Formula I may be
admixed as a dry powder with a dry gelatin binder in an approximate
1:2 weight ratio. A minor amount of magnesium stearate may be added
as a lubricant. The mixture may be formed into 450-900 mg tablets
(150-300 mg of active compound of the invention according to
Formula I) in a tablet press.
Formulation 5--Injection
[1123] A compound of the invention according to Formula I may be
dissolved or suspended in a buffered sterile saline injectable
aqueous medium to a concentration of approximately 5 mg/mL.
Formulation 6--Topical
[1124] Stearyl alcohol (250 g) and a white petrolatum (250 g) may
be melted at about 75.degree. C. and then a mixture of A compound
of the invention according to Formula I (50 g) methylparaben (0.25
g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and
propylene glycol (120 g) dissolved in water (about 370 g) may be
added and the resulting mixture may be stirred until it
congeals.
Methods of Treatment
[1125] In one embodiment, the present invention provides compounds
of the invention, or pharmaceutical compositions comprising a
compound of the invention, for use in the prophylaxis and/or
treatment of one or more fibrotic diseases. In a particular
embodiment, the fibrotic disease is NASH and/or NAFLD. In a most
particular embodiment, the fibrotic disease is NASH. In another
most particular embodiment, the fibrotic disease is idiopathic
pulmonary fibrosis (IPF).
[1126] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of one
or more fibrotic diseases. In a particular embodiment, the fibrotic
disease is NASH and/or NAFLD. In a most particular embodiment, the
fibrotic disease is NASH. In another most particular embodiment,
the fibrotic disease is idiopathic pulmonary fibrosis (IPF).
[1127] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
afflicted with fibrotic diseases, which methods comprise the
administration of an effective amount of a compound of the
invention or one or more of the pharmaceutical compositions herein
described for the treatment or prophylaxis of said condition. In a
particular embodiment, the fibrotic disease is NASH and/or NAFLD.
In a most particular embodiment, the fibrotic disease is NASH. In
another most particular embodiment, the fibrotic disease is
idiopathic pulmonary fibrosis (IPF).
[1128] In one embodiment, the present invention provides
pharmaceutical compositions comprising a compound of the invention,
and another therapeutic agent. In a particular embodiment, the
other therapeutic agent is a fibrotic disease treatment agent. In a
particular embodiment, the fibrotic disease is NASH and/or NAFLD.
In a most particular embodiment, the fibrotic disease is NASH. In
another most particular embodiment, the fibrotic disease is
idiopathic pulmonary fibrosis (IPF).
[1129] In one embodiment, the present invention provides compounds
of the invention, or pharmaceutical compositions comprising a
compound of the invention, for use in the prophylaxis and/or
treatment of a subject presenting a NAS score of at least 3, at
least 4, at least 5, at least 6 or at least 7.
[1130] In another embodiment, the present invention provides
compounds of the invention, or pharmaceutical compositions
comprising a compound of the invention for use in the manufacture
of a medicament for use in the prophylaxis and/or treatment of a
subject presenting a NAS score .gtoreq.5.
[1131] In additional method of treatment aspects, this invention
provides methods of prophylaxis and/or treatment of a mammal
presenting a NAS score .gtoreq.5, which methods comprise the
administration of an effective amount of a compound of the
invention or one or more of the pharmaceutical compositions herein
described for the treatment or prophylaxis of said fibrotic
diseases, in particular NASH, and/or NAFLD, more particularly
NASH.
[1132] In further method of treatment embodiments, the methods of
prophylaxis and/or treatment of a mammal comprises measuring the
forced vital capacity (FVC) in the subject, wherein the FVC does
not decrease following treatment. In a particular embodiment, FVC
does not decrease over a period of 12, 16, 20 or 26 weeks of
treatment.
[1133] In another embodiment, the method comprises measuring the
FVC in the subject, wherein the FVC increases by at least 1 mL, at
least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 6
mL, at least 7 mL or at least 8 mL. In a particular embodiment, the
FVC increases by at least 1 mL, at least 2 mL, at least 3 mL, at
least 4 mL, at least 5 mL, at least 6 mL, at least 7 mL or at least
8 mL over a period of 12, 16, 20 or 26 weeks of treatment.
[1134] In one embodiment, the method comprises measuring the airway
volume wherein said airway volume decrease is no more than 5 mL/L,
no more than 4 mL/1, or no more than 3 mL/L. In a particular
embodiment the airway volume decrease is no more than 5 mL/L, no
more than 4 mL/1, or no more than 3 mL/L after 12, 16, 20 or 26
weeks of treatment.
[1135] Injection dose levels range from about 0.1 mg/kg/h to at
least 10 mg/kg/h, all for from about 1 to about 120 h and
especially 24 to 96 h. A preloading bolus of from about 0.1 mg/kg
to about 10 mg/kg or more may also be administered to achieve
adequate steady state levels. The maximum total dose is not
expected to exceed about 1 g/day for a 40 to 80 kg human
patient.
[1136] For the prophylaxis and/or treatment of long-term
conditions, such as degenerative conditions, the regimen for
treatment usually stretches over many months or years so oral
dosing is preferred for patient convenience and tolerance. With
oral dosing, one to four (1-4) regular doses daily, especially one
to three (1-3) regular doses daily, typically one to two (1-2)
regular doses daily, and most typically one (1) regular dose daily
are representative regimens. Alternatively for long lasting effect
drugs, with oral dosing, once every other week, once weekly, and
once a day are representative regimens. In particular, dosage
regimen can be every 1-14 days, more particularly 1-10 days, even
more particularly 1-7 days, and most particularly 1-3 days.
[1137] Using these dosing patterns, each dose provides from about 1
to about 1000 mg of a compound of the invention, with particular
doses each providing from about 10 to about 500 mg and especially
about 30 to about 250 mg. In a particular embodiment, a compound of
the invention is administered in a 30 to 250 mg (such as 100 mg)
daily dose for the treatment and/or prevention of fibrotic disease,
more in particular the treatment and/or prevention of NASH, or, the
treatment of IPF. In a further and most particular embodiment, said
compound of the invention is
9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimi-
do[6,1-a]isoquinolin-4-one.
[1138] Transdermal doses are generally selected to provide similar
or lower blood levels than are achieved using injection doses.
[1139] When used to prevent the onset of a condition, a compound of
the invention will be administered to a patient at risk for
developing the condition, typically on the advice and under the
supervision of a physician, at the dosage levels described above.
Patients at risk for developing a particular condition generally
include those that have a family history of the condition, or those
who have been identified by genetic testing or screening to be
particularly susceptible to developing the condition.
[1140] A compound of the invention can be administered as the sole
active agent or it can be administered in combination with other
therapeutic agents, including other compound of the inventions that
demonstrate the same or a similar therapeutic activity and that are
determined to be safe and efficacious for such combined
administration. In a specific embodiment, co-administration of two
(or more) agents allows for significantly lower doses of each to be
used, thereby reducing the side effects seen.
[1141] In one embodiment, a compound of the invention or a
pharmaceutical composition comprising a compound of the invention
is administered as a medicament. In a specific embodiment, said
pharmaceutical composition additionally comprises a further active
ingredient.
[1142] In one embodiment, a compound of the invention is
co-administered with one or more further therapeutic agents for the
treatment and/or prophylaxis of a fibrotic disease. In a particular
embodiment, a compound of the invention is co-administered with one
or two further therapeutic agents for the treatment and/or
prophylaxis of a fibrotic disease. In a more particular embodiment,
a compound of the invention is co-administered with one further
therapeutic agent for the treatment and/or prophylaxis of a
fibrotic disease.
[1143] In one embodiment, the further therapeutic agent for the
treatment and/or prophylaxis of a fibrotic disease include, but are
not limited to 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone);
nintedanib (Ofev.RTM. or Vargatef.RTM.); STX-100
(ClinicalTrials.gov Identifier NCT01371305), FG-3019
(ClinicalTrials.gov Identifier NCT01890265), lebrikizumab (CAS n
#953400-68-5); tralokinumab (CAS n #1044515-88-9), CC-90001
(ClinicalTrials.gov Identifier NCT03142191), tipelukast (MN-001;
ClinicalTrials.gov Identifier NCT 02503657), ND-L02-s0201
(ClinicalTrials.gov Identifier NCT03538301), KD025
(ClinicalTrials.gov Identifier NCT 02688647), TD139
(ClinicalTrials.gov Identifier NCT02257177), VAY736
(ClinicalTrials.gov Identifier NCT03287414), PRM-151
(ClinicalTrials.gov Identifier NCT02550873) and PBI-4050
(ClinicalTrials.gov Identifier NCT02538536). In a particular
embodiment, the further therapeutic agent for the treatment and/or
prophylaxis of a fibrotic disease is an autotaxin (or
ectonucleotide pyrophosphatase/phosphodiesterase 2 or NPP2 or
ENPP2) inhibitor, examples of which are described in WO
2014/139882, such as GLPG1690.
[1144] In one embodiment, a compound of the invention is
co-administered with another therapeutic agent for the treatment
and/or prophylaxis of NASH, particular agents include but are not
limited to weight loss treatment agents (for example Sibutramine,
or Orlistat), insulin-sensitizing agents (for example Metformin,
Thiazolidinedione, Rosiglitazone, or Pioglitazone), lipid-lowering
agents (for example Gemfibrozil), Antioxidants (for example
Vitamine E, N-acetylcysteine, Betaine, or Pentoxifylline),
Angiotensin-converting enzyme inhibitors, Angiotensin-receptor
blockers, Monounsaturated fatty acids, or Polyunsaturated fatty
acids. FXR agonists (for example Obeticholic acid), LOXL2
antagonists (for example Simtuzumab), ASK1 antagonists (for example
Selonsertib), PPAR agonists (for example clofibrate, gemfibrozil,
ciprofibrate, bezafibrate, fenofibrate, thiazolidinediones,
ibuprofen, GW-9662, aleglitazar, muraglitazar or tesaglitazar),
Acetyl CoA-Carboxylase (ACC) antagonists (for example NDI-010976,
PF-05221304), CCR2/CCR5 (for example Cenicriviroc), VAP1
antagonist.
[1145] In a more particular embodiment, the further therapeutic
agent is selected from GLPG1690, or one or more of the compounds of
WO 2017/148787. By co-administration is included any means of
delivering two or more therapeutic agents to the patient as part of
the same treatment regime, as will be apparent to the skilled
person. Whilst the two or more agents may be administered
simultaneously in a single formulation, i.e. as a single
pharmaceutical composition, this is not essential. The agents may
be administered in different formulations and at different
times.
BIOLOGICAL EXAMPLES
[1146] The methods for the preparation of the compounds of the
invention have been described in WO 2013/092791, WO 2014/095798, WO
2015/197550, and WO 2016/169911.
Example 1. In Vitro Assays
[1147] The in vitro activity on GPR84 and on neutrophil migration
of the compounds of the invention have been described in WO
2013/092791, WO 2014/095798, WO 2015/197550, and WO
2016/169911.
Example 2. Cellular Assay
2.1. Neutrophil Migration Assay
[1148] Whereas GPR84 agonists (MCFA such as sodiumdecanoate, 3,3'
di indolylmethane and Embelin) may induce neutrophil chemotaxis and
GPR84 antagonists may block GPR84 agonist-induced chemotaxis but
not IL8-induced chemotaxis, it follows that G Protein-Coupled
Receptor 84 (GPR84) is linked to neutrophil recruitment.
[1149] The effect of agonists or antagonists for GPR84 can
therefore be assayed in a neutrophil migration test. In the
neutrophil migration assay, neutrophils, freshly isolated from
buffy coats from human volunteers, are treated with a test compound
for 30 minutes. Subsequently, the neutrophils are transferred to
the upper wells of a Corning HTS transwell 96 permeable support
system, of which the lower wells are filled with a embelin solution
at ECK) (concentration which gives 80% of the activity of GPR84).
After 1 h of incubation, migration of the neutrophils towards
embelin in the lower compartment can be quantified by measuring the
ATP-content of the lower wells using the ATPlite luminescence ATP
detection assay system (Perkin Elmer, Cat. No.: 436110).
2.1.1. Isolation of Neutrophils from Human Huffy Coat
[1150] A human buffy coat is diluted with an equal volume of ice
cold DPBS. 20 mL of the diluted buffy coat is gently mixed with 4
mL of ACD buffer (140 mM citric acid, 200 mM sodium citrate and 220
mM dextrose). Then, 12 mL of the 6% dextran/0.9% NaCl solution (15
g dextran T2000 and 2.25 g NaCl dissolved in 250 mL H.sub.2O) is
added to the mixture and the samples are inverted gently up to 20
times. The total volume is transferred to a new recipient and
incubated at room temperature for 1 h for complete separation of
the two phases to occur. The supernatant is then transferred to a
clean centrifugation tube and centrifuged for 12 minutes at 1300
rpm and 4.degree. C. After centrifugation, the supernatant is
discarded and the remaining cell pellet is rapidly resuspended in
12 mL of ice-cold H.sub.2O for red blood cell lysis to occur. After
20 seconds, 4 mL of ice-cold 0.6 M KCl is added. Samples are mixed
carefully and centrifuged for 6 minutes at 1300 rpm, 4.degree. C.
The supernatant is discarded and the red blood cell lysis procedure
is repeated one more time. Subsequently, the cell pellet is
resuspended in 4 mL of DPBS and layered over 5 mL of Lymphoprep
(Nycomed Pharma, Cat. No.: 1114545) in a 15 mL centrifuge tube.
After centrifugation for 12 min at 1300 rpm, 4.degree. C., the
supernatant is removed and the cell pellet, containing the
neutrophils, is resuspended in 25 mL chemotaxis buffer (RPMI 1640
medium, supplemented with 10 mM HEPES; freshly made for each
experiment)
2.1.2. Migration Assay
[1151] A cell suspension of 8.9.times.106 cells per milliliter is
prepared. 20 .mu.L of compound solution in chemotaxis buffer is
added to 180 .mu.L cell suspension. The mixture is incubated at
37.degree. C. for 30 minutes with intermediate resuspension of the
cells after 15 minutes. Following this, 70 .mu.L cell suspension is
transferred to the upper compartment of a Corning HTS transwell 96
permeable support system with 5.0 .mu.m pore size polycarbonate
membrane (Corning, Cat. No.: 3387). The receiver well of the
transwell system is then filled with 200 .mu.L chemotaxis buffer
containing compound and chemotactic agent (embelin). After
incubation at 37.degree. C. in 5% CO.sub.2 for 1 h, the upper plate
of the transwell system is removed and the cell suspension in the
receiver plate is transferred to a 96-well V-bottom plate. 50 .mu.L
of DPBS is added to the receiver plate to prevent remaining cells
from drying out. The V-bottom plate is centrifuged for 6 minutes at
1500 rpm. The supernatant is removed and the cells are resuspended
in 50 .mu.L DPBS. The cells are then transferred back to the
receiver plate of the transwell system. After this, 100 .mu.L
ATPlite solution (Perkin Elmer, Cat. No: 436110) is added to the
cells. The plate is incubated for 10 minutes in the dark, while
shaking. 170 .mu.L of cell lysate is then transferred to a white
96-well plate and luminescence is measured. The detected
luminescent signal is considered as linearly related to the number
of cells having migrated from the upper well to the receiver
well.
Example 3. In Vivo Assays
3.1. Materials
[1152] In the following illustrative examples, the following
compounds are tested, the syntheses of which are disclosed in WO
2013/092791 and WO 2016/169911:
##STR00024##
3.2. CCl.sub.4 Model
[1153] A single dose of CCl4 leads to centrizonal necrosis and
steatosis, while prolonged administration leads to liver fibrosis,
cirrhosis, and hepatocellular carcinoma. (Fujii et al., 2010)
[1154] At initiation, 5 weeks-old Male Balb/cJ mice (Janvier Labs,
France) maintained at 22.degree. C..+-.2.degree. C. and humidity at
55%.+-.10%, with a 12-hrs dark/light cycle. All mice are fed a
standard diet (chow (A04C-10, Safe, France). All animals have
access to filtered tap drinking water.
[1155] Twice a week, mice are injected intraperitoneally with 0.6
mL/kg of CCl.sub.4 (319961, SIGMA) diluted at 1/2 in olive oil
(01514, SIGMA) for 6 weeks. Control group 1 (C1) animals are
injected with olive oil. Control group 2 (C2) animals are also
injected with CCl.sub.4 in olive oil.
[1156] Three weeks after the initiation, animals are assigned to a
test-group or a control-group. Test group animals are dosed with a
test compound at 30 mg/kg, i.e. Compound A (CpdA) or Compound B
(CpdB), q.d., p.o. formulated in methylcellulose 0.5%, 1 equivalent
HCl. The control groups receive a similar volume of vehicle (10
mL/kg).
[1157] After sacrifice (week 6), the activity of the test compound
on the development of fibrosis is evaluated in liver by
histopathological examination of fibrosis (Sirius red), collagen
(OH-Pro) dosage and expression of fibrotic and inflammatory
genes.
[1158] FIG. 1 shows the effect of Compound A (CpdA) and Compound B
(CpdB) on CCl.sub.4 induced necrosis in the liver. FIG. 2 shows the
F4/80 glycoprotein stained area fraction [%] observed in liver
samples from the animals tested. The F4/80 glycoprotein is a murine
macrophage specific cell-surface biomarker. FIG. 3 shows the
percentage of neutrophils (panel A) and of monocytes (panel B) in
total leucocyte cell population of blood samples obtained from the
tested animals FIG. 4 shows the percentage of neutrophils (panel
A), of monocytes (panel B) and of monocytic macrophages (MoMF,
panel C) in total leucocyte cell population of liver samples
obtained from the tested animals.
3.3. MCD Model
[1159] The methionine and choline deficient (MCD) diet model is
used to produce a severe phenotype of NASH in a time (Santhekadur
et al., 2017), and is used to evaluate the compounds of the
invention.
[1160] At induction, 8 weeks-old male C57BL/6 mice (Janvier Labs,
France) maintained at 22.degree. C..+-.2.degree. C. and humidity at
55%.+-.10%, with a 12-hrs dark/light cycle are fed a standard diet
(chow (A04C-10, Safe, France) or a Methionine and Choline-deficient
(MCD) diet (EFTD.90262, Ssniff, Soest, Germany) for 8 weeks. All
animals have access to filtered tap drinking water.
[1161] Four weeks after the induction, the animals are either
assigned to a control-group or a test-group.
[1162] Test group animals are dosed with the a test compound, i.e.
Compound A (CpdA) or Compound B (CpdB), at 30 mg/kg, q.d., p.o.
formulated in methylcellulose 0.5%, 1 equivalent HCl. The control
groups receives a similar volume of vehicle (10 mL/kg), i.e. the
standard diet for control group 1 (C1) and the MCD diet for control
group 2 (C2). Mice are randomly assigned to a treatment group
according to their body weight in order to ensure a homogenous
reparation.
[1163] FIG. 5 shows the necrotic area fraction [%] observed in
liver samples obtained from the tested animals FIG. 6 shows the
F4/80 stained area fraction [%] observed in liver samples. FIG. 7
shows Fluorescence-activated cell sorting (FACS) results measured
in blood and liver samples obtained from animals in control group 1
(C1), control group 2 (C2), test group dosed with Compound A (CpdA)
and test group dosed with Compound B (CpdB) for CD4 cells (Panel
A), CD8 cells (Panel B), Blood monocyte (Panel C), Liver
neutrophils cells (Panel D), Liver infiltrating monocyte-derived
macrophage (MoMF) cells (Panel E), Liver CD19 cells (Panel F),
Liver Natural Killer (NK) cells (Panel G), Liver Natural Killer T
(NKT) cells (Panel H), and liver Kupfer cells (Panel I). FIG. 8
shows gene expression of Colla1 (panel A) and Timp1 (panel B) in
blood samples. FIG. 9 shows gene expression of TNF.alpha. (panel A)
and CCL2 (panel B) in the liver.
[1164] After sacrifice (week 8), the activity of the test compound
on the development of NASH is assessed by plasma ALT and AST levels
and in liver by histopathological examination of fibrosis and
steatosis (Sirius red, Oil Red O), collagen (OH-Pro) and
triglycerides content and expression of fibrotic and inflammatory
genes.
[1165] In addition, the NAS score is determined to further evaluate
the compounds with respect to their effect on diet induced NASH.
The nonalcoholic fatty liver disease activity scoring (NAS) has
been proposed and accepted as a tool to measure changes in NAFLD
during therapeutic trials (Brunt et al., 2011; Kleiner et al.,
2005).
[1166] The NAS score (0-8) is defined as the sum of the steatosis
score (0-3), lobular inflammation score (0-3), ballooning score
(0-2). A NAS score of .gtoreq.5 is indicative of a NASH diagnostic.
FIG. 10 shows NAS scores as obtained in tested animals.
TABLE-US-00001 TABLE I Col1a NRQ gene expression-FIG. 8 Panel A 8
weeks MCD Compound A (CpdA) Compound B (CpdB) chow diet 8 wk (30
mg/kg) 8 wk (30 mg/kg) 8 wk 0.1 1.9 2.1 0.3 0.1 1.3 0.6 0.2 0.1 0.6
2.4 0.3 0.1 1.1 0.8 0.2 0.2 1.1 0.3 0.5 0.1 1.5 0.8 2.0 0.0 0.6 1.0
1.3 0.0 0.9 0.5 1.5 0.1 1.0 0.1 1.5 0.0 0.7 0.4 0.4
TABLE-US-00002 TABLE II TIMP1 NRQ gene expression-Fig 8 Panel B 8
Compound A Compound B weeks (CpdA) (CpdB) chow MCD (30 mg/kg) (30
mg/kg) diet 8 wk 8 wk 8 wk 0.1 1.6 2.3 0.3 0.1 1.3 0.4 0.3 0.3 0.6
1.0 0.3 0.0 1.2 1.1 0.4 0.1 1.3 0.4 0.5 0.1 0.7 0.8 1.7 0.0 0.6 0.9
1.2 0.0 1.2 0.4 1.4 0.1 1.1 0.1 1.7 0.0 0.8 0.5 0.4
TABLE-US-00003 TABLE III TNf.alpha. NRQ gene expression-Fig 9 Panel
A 8 Compound A Compound B weeks (CpdA) (CpdB) chow MCD (30 mg/kg)
(30 mg/kg) diet 8 wk 8 wk 8 wk 0.1 1.3 1.5 0.3 0.1 0.9 0.4 0.3 0.1
1.0 0.8 0.4 0.1 1.1 1.4 0.4 0.1 1.2 0.8 0.7 0.0 1.2 1.0 1.1 0.1 0.8
0.7 0.8 0.1 1.0 0.5 1.1 0.0 0.9 0.1 0.9 0.0 0.9 0.8 0.6
TABLE-US-00004 TABLE IV CC12 NRQ gene expression-Fig 9 Panel B 8
Compound A Compound B weeks (CpdA) (CpdB) chow MCD (30 mg/kg) (30
mg/kg) diet 8 wk 8 wk 8 wk 0.0 1.4 1.0 0.5 0.1 1.1 0.6 0.7 0.0 0.8
0.5 0.8 0.1 1.1 1.2 0.3 0.0 1.0 0.6 0.7 0.1 0.9 0.5 1.2 0.1 1.3 0.7
0.9 0.0 0.8 0.5 1.2 0.0 0.9 0.2 1.5 0.0 1.0 0.5 0.9
TABLE-US-00005 TABLE V NAS scoring data-Fig 10 8 Compound A
Compound B weeks (CpdA) (CpdB) chow MCD (30 mg/kg) (30 mg/kg) diet
8 wk 8 wk 8 wk 0.0 7.0 8.0 6.0 1.0 8.0 6.0 6.0 1.0 6.0 7.0 5.0 1.0
8.0 6.0 7.0 0.0 7.0 7.0 6.0 1.0 7.0 6.0 7.0 1.0 7.0 6.0 6.0 1.0 8.0
7.0 6.0 1.0 8.0 5.0 6.0 1.0 8.0 7.0 6.0
3.4. CDAHFD Model
[1167] The choline-deficient, L-amino acid-defined, high-fat diet
(CDAHFD) dietary model is another model that develops
steatohepatitis, liver fibrosis and hepatocarcinogenesis similar to
MCD diet (Santhekadur et al., 2017) and is used to evaluate the
compounds of the invention.
[1168] At induction, 8 weeks-old male C57BL/6 mice (Janvier Labs,
France) maintained at 22.degree. C..+-.2.degree. C. and humidity at
55%.+-.10%, with a 12-hrs dark/light cycle are fed a standard chow
diet (A04C-10, SAFE, France) or choline deficient diet with 0.1%
methionine (CDAHF) diet (A06071302, Research Diet, USA) for 8
weeks. All animals have access to filtered tap drinking water.
[1169] Four weeks after the induction, the animals are either
assigned to a control-group or the test-group. Mice are randomly
assigned to a treatment group according to their body weight in
order to ensure a homogenous reparation. Test group animals are
dosed with the test compound, i.e. Compound A (CpdA), at 30 mg/kg,
q.d., p.o. formulated in methylcellulose 0.5%, 1 equivalent HCl.
The control groups receives a similar volume of vehicle (10 mL/kg),
i.e. the standard diet for control group 1 (C1) and the CDAHF diet
for control groups 2 (C2, 8 weeks) and the CDAHF diet+Elafibranor
dosed at 30 mg/kg, q.d., p.o. formulated in 0.1% Tween 80+1% methyl
cellulose+98.9% water (CpdC, 10 weeks).
[1170] After sacrifice (week 8), the activity of the test compound
on the development of NASH is assessed by plasma ALT and AST levels
and in liver by histopathological examination of fibrosis and
steatosis (Sirius red, Oil Red O), collagen (OH-Pro) and
triglycerides content and expression of fibrotic and inflammatory
genes. FIG. 11 reports on the observed effect of the Compound A
(CpdA) on CDAHF diet induced formation of fibrotic tissue in the
liver. FIG. 12, panel A illustrates the effect of Compound A (CpdA)
on CDAHF diet gene expression profiles of Colla1. FIG. 12, panel B
illustrates the effect of Compound A (CpdA) on CDAHF diet gene
expression profiles of TNF.alpha..
TABLE-US-00006 TABLE VI Fibrosis (Sirius red area %)-Figure 11 Chow
CDAHFD diet l0W- 10W- CDAHFD CDAHFD CDAHFD Compound A vehicle
8W-vehicle 10W-vehicle l0W-CpdC (CpdA) 0.09 0.67 1.10 0.52 0.97
0.02 0.45 1.07 0.32 0.59 0.04 0.40 0.68 0.45 0.53 0.04 0.58 0.84
0.19 0.89 0.03 0.66 0.82 0.41 0.77 0.05 1.01 0.55 0.75 0.46 0.04
0.56 1.06 0.55 0.67 0.04 0.89 2.09 0.32 0.53 0.06 0.42 0.96 0.26
0.80 0.06 0.48 1.55 nd 0.64 nd: not determined
TABLE-US-00007 TABLE VII Col1a1 expression profiles (NRQ-scaled
versus Disease-Vehicle)-Fig 12 panel A Chow CDAHFD diet l0W- 10W-
CDAHFD CDAHFD CDAHFD Compound A vehicle 8W-vehicle 10W-vehicle
l0W-CpdC (CpdA) 0.01 1.01 0.82 0.61 0.12 0.02 0.80 1.57 0.17 0.26
0.06 1.54 0.67 0.07 1.76 0.11 0.70 1.79 0.06 0.36 0.04 0.13 2.08 nd
0.49 0.12 0.09 1.16 0.48 0.35 0.13 0.63 0.19 0.15 0.43 0.05 0.74
0.41 0.09 0.38 0.02 0.21 1.30 0.43 0.10 0.02 0.78 2.72 nd 0.18 nd:
not determined
TABLE-US-00008 TABLE VIII TNF.alpha. expression profiles
(NRQ-scaled versus Disease-Vehicle)-Figure 12 panel B Chow CDAHFD
diet l0W- 10W- CDAHFD CDAHFD CDAHFD Compound A vehicle 8W-vehicle
10W-vehicle l0W-CpdC (CpdA) 0.09 0.67 1.10 0.52 0.97 0.02 0.45 1.07
0.32 0.59 0.04 0.40 0.68 0.45 0.53 0.04 0.58 0.84 0.19 0.89 0.03
0.66 0.82 0.41 0.77 0.05 1.01 0.55 0.75 0.46 0.04 0.56 1.06 0.55
0.67 0.04 0.89 2.09 0.32 0.53 0.06 0.42 0.96 0.26 0.80 0.06 0.48
1.55 nd 0.64 nd: not determined
3.5. Therapeutic Bleomycin Induced Pulmonary Fibrosis 21-Day Mice
Model
[1171] The aim of the study is to test the efficacy of a test
compound at three different doses in a 21-day model of bleomycin
induced pulmonary fibrosis in mice.
3.5.1. Animals
[1172] 11 week-old C57BL/6N male mice from Charles River (Italy)
are maintained on 12 h light/dark cycle at 22.degree. C. with ad
libidum access to tap water and food.
[1173] At least one day prior to start of experiment, all animals
are allocated randomly into groups as indicated in the table
below.
[1174] On day 0, all mice in groups 2-4 receive a 1.5 U/kg
oropharyngeal administration of bleomycin (BLM) to induce pulmonary
fibrosis Animals in group 1 are not administered bleomycin, but
instead receive a single dose of saline via the oropharyngeal
route, and are considered sham control mice.
TABLE-US-00009 TABLE IX Study groups Treatment schedule Groups
Purpose n Dose Days (Frequency) Route Vehicle 1 control 10 -- D 7-D
21 (QD) PO 0.1% Natrosol Sham + vehicle 2 control 15 -- D 7-D 21
(QD) PO 0.1% Natrosol BLM + vehicle 3 control 15 60 D 7-D 21 (QD)
PO 0.1% Natrosol BLM + nintedanib mg/kg 4 active 15 30 D 7-D 21
(BID) PO 0.5% BLM + CpdA mg/kg methylcellulose
3.5.2. Study
[1175] Animals are examined clinically twice daily. List of
clinical signs and parameters are indicated in humane endpoints
table. Animals are weighed daily starting from DO.
[1176] On day 21, lung functionality is determined. After deep
anesthesia induced by an intraperitoneal injection (10 mL/kg) of a
solution of xylazine (5 mg/kg) and ketamine (75 mg/kg), the trachea
is exposed through midline incision and a cannula is inserted. Mice
are ventilated with a tidal volume of 10 mL/kg at a frequency of
150 breaths/minute. FlexiVent (SCIREQ.RTM.) perturbations are
performed three times. Deep Inflation and Pressure-Volume loops (PV
loops) with stepwise increasing pressure are performed to measure
the Inspiratory Capacity and stepwise pressure-driven perturbation
(PVs-P). PV loops between 0 and 30 cm H.sub.2O are generated to
obtain Total Lung Capacity (A). A snapshot perturbation maneuver is
imposed, which is a threefold sinusoidal wave of in- and expiration
controlled by the ventilator, resulting in resistance (Rrs),
compliance (Crs), and elastance (Ers) of the whole respiratory
system (airways, lung and chest wall). A value for each group is
calculated with average FlexiVent-validated measurements recorded
in each individual subject.
[1177] Then, two hours after the last dose of test substance and
nintedanib, mice are sacrificed by anesthetic overdose. The lungs
are excised and weighed individually. The lungs are then placed
into marked bottles containing 10% buffered formalin for further
histopathological evaluation.
3.5.3. Sample Analysis, Data Processing and Statistical
Evaluation
[1178] Body weight data and lung weight data are processed using MS
Excel. Statistical analysis and graphical presentation are
performed using GraphPad Prism software (version 5.04).
[1179] One-way ANOVA or Mann-Whitney tests are employed for lung
weights.
[1180] Two-way ANOVA tests are employed for body weight
changes.
[1181] Differences between groups are considered statistically
significant when p<0.05.
[1182] For histopathological evaluation, whole lungs are embedded
in paraffin and stained with Mallory's trichrome.
[1183] Pulmonary histological changes are assessed using Matsuse's
modification of Ashcroft score (Ashcroft et al., 1988; Matsuse et
al., 1999). Statistical analysis and graphical presentation is
performed using GraphPad Prism software (version 5.04).
Mann-Whitney test is employed.
[1184] Differences between groups are considered statistically
significant when p<0.05.
TABLE-US-00010 Ashcroft Score 1 Normal lungs (no fibrosis) 2
Minimal fibrotic thickening of alveolar or bronchial walls (network
of fine collagen fibrils) 3 Moderate fibrotic thickening of walls
without obvious damage to lung architecture 4 Fibrosis with damage
of pulmonary structure (coarse fibrous bands or small fibrous
masses, intra-alveolar collagen fibrils) 5 Large fibrous area with
severe distortion of lung structure
TABLE-US-00011 TABLE X Ashcroft Score-Figure 13 BLM- BLM- BLM-
Intact vehicle nintedanib CpdA 1.0 2.4 3.0 3.4 1.0 4.0 3.5 2.3 1.0
3.8 2.4 2.0 1.0 nd 3.7 2.1 1.0 3.9 2.0 nd 1.0 3.4 2.3 2.4 1.0 3.6
2.8 3.0 1.0 3.1 3.2 2.5 1.0 nd 3.7 3.3 1.0 4.0 3.5 3.4 1.9 3.5 2.9
4.0 3.0 2.9 2.7 3.4 2.7 3.3 3.5 3.6 nd 2.5 2.7 nd: not
determined
TABLE-US-00012 TABLE XI Inspiratory Capacity (mL)-Figure 14 panel A
BLM- BLM- BLM- Intact vehicle nintedanib CpdA 0.74 nd 0.76 0.84 nd
0.47 0.78 0.73 0.89 0.50 nd 0.69 0.84 nd 0.33 0.71 0.75 0.52 0.69
nd 0.70 0.51 0.57 nd 0.73 0.49 0.62 0.58 0.86 0.48 0.71 0.66 nd nd
nd nd nd nd 0.48 nd nd nd 0.65 0.28 0.58 0.59 0.70 0.68 0.75 0.50
0.53 0.58 nd 0.56 0.69 nd: not determined
TABLE-US-00013 TABLE XII Compliance of the Respiratory System
(mL/cmH.sub.2O)-Figure 14 panel B BLM- BLM- BLM- Intact vehicle
nintedanib CpdA 0.043 nd 0.039 0.046 nd 0.025 0.045 0.042 0.046
0.026 nd 0.041 0.045 nd 0.015 nd 0.040 0.027 0.039 nd 0.038 0.027
0.031 0.034 0.042 0.025 0.032 0.030 0.045 0.024 0.040 0.035 nd nd
nd 0.037 nd nd 0.027 nd nd 0.027 0.036 nd 0.032 0.033 0.042 0.034
0.041 0.026 0.027 0.031 nd 0.035 0.038 nd: not determined
TABLE-US-00014 TABLE XIII Elastance of the Respiratory System
(cmH.sub.2O/mL)-Figure 14 panel C BLM- BLM- BLM- Intact vehicle
nintedanib CpdA 23.18 nd 25.68 21.92 nd 40.71 nd 23.92 21.90 38.14
22.39 24.49 22.34 nd 68.28 nd 25.00 36.93 25.83 nd 26.52 37.20
32.61 29.43 23.84 38.89 31.04 33.18 22.21 42.23 25.16 28.94 nd nd
nd 26.99 nd nd 37.06 nd nd 36.60 27.50 nd 31.06 30.18 24.02 29.07
24.40 38.70 37.31 31.90 nd 28.26 26.35 nd: not determined
3.6. Radiation Induced Fibrosis Mice Model
3.6.1. Study Overview
[1185] Pneumonitis and lung fibrosis are the major
radiation-induced complications following thoracic radiotherapy,
which is one of the major treatment of lung and breast cancers,
lymphomas and hematopoietic transplant conditioning.
[1186] The objective of this model is to evaluate the effect of a
compound of the invention in lung fibrosis induced by radiation in
mice. (Bickelhaupt et al., 2017)
TABLE-US-00015 TABLE XIV Study groups Treatment schedule Groups
Purpose n Dose Days (Frequency) Route Vehicle 1 control 10 -- D 1-D
14 (QD) PO 0.1% Natrosol Sham + vehicle 2 control 12 -- D 1-D 14
(QD) PO 0.1% Natrosol Irradiated + vehicle 3 control 12 60 D 1-D 14
(QD) PO 0.1% Natrosol Irradiated + nintedanib mg/kg 4 active 12 30
D 1-D 14 (QD) PO 0.5% BLM + CpdA mg/kg methylcellulose
3.6.2. Animals
[1187] 7 weeks old (18/22 gr) female C57BL/6J mice from Charles
River (France) are maintained on 12 h light/dark cycle at
22.degree. C. with ad libidum access to tap water and food.
3.6.3. Materials
[1188] The test compounds are dissolved/suspended in appropriate
vehicle prior to using and then kept light-free, under agitation at
room temperature.
[1189] An aliquot of the formulation (approx. 200 .mu.L) is frozen
at TO (day of preparation) and all the formulations are checked
(daily) for any change in aspect.
[1190] The dose volume administered is 10 mL/kg and the volume is
adapted following mean body weight (BW) of the group as follows:
200 .mu.L if mean BW<22.5 g, 250 .mu.L if mean BW.gtoreq.22.5 g;
300 .mu.L if mean BW>27.5 g.
3.6.4. In Vivo Experimental Procedure
[1191] On day 1 of week 1, the animals are exposed at the thorax to
a 17 Gray irradiation dose, under isoflurane anesthesia.
[1192] At the beginning of week 18 post irradiation (Day 1),
animals are randomized into 4 study groups (12 subjects per group,
except sham group: 10 subjects): 1) sham (vehicle: methylcellulose
0.5%), 2) diseased (vehicle: methylcellulose 0.5%), 3) positive
control (nintedanib 60 mg/kg in 0.1% Natrosol), and 4) test
compound (30 mg/kg CpdA in 0.5% methylcellulose), and dosed p.o.
q.d until Day 14 (week 21).
[1193] Body weight are recorded once a week, and on Day 14, lung
function measurement under anesthesia is realized by Flexivent
(Devos et al., 2017) for all groups before sacrifice.
3.6.5. Histology Procedures
3.6.5.1. Type I Collagen Quantification
[1194] At sacrifice on Day 14, the lungs are collected and fixed in
4% formaldehyde for 24 h before embedding in paraffin. 4 .mu.m
thick sections are immunostained with anti-collagen I antibody
(LifeSpan Biosciences, Cat. No: LS-C.sub.3-43921). The sections are
deparaffinized and processed by heat-induced antigen retrieval
before incubation one hour with the primary antibody. The
anti-collagen I antibody is detected and amplified by ImmPress kit
(Vector Laboratories, Cat. No: MP-7401). The immunostained sections
are then scanned (Nanozoomer 2.0HT, Hamamatsu) before
quantification by image analysis (CaloPix software, TRIBVN
Healthcare). Data are expressed as percentage collagen I area per
area of lung tissue.
[1195] Values for all mice from the same group are averaged. Data
are expressed as mean.+-.sem and are compared with a one-way ANOVA
followed by Dunnett multiple comparison post hoc test.
3.6.5.2. Oxidative Stress: MnSOD Quantification
[1196] Oxidative stress is a key player in the pathogenesis of IPF
(Matsuzawa et al., 2015) and fibrosis (Richter and Kietzmann,
2016).
[1197] Manganese superoxide dismutase (MnSOD), located in
mitochondria, catalyzes the conversion of superoxide into
H.sub.2O.sub.2, and is a marker of antioxidant response induced by
oxidative stress. MnSOD expression is measured
immunohistochemically following a protocol adapted from Inghilleri
et al. (Inghilleri et al., 2006).
[1198] At sacrifice on Day 14, the lungs are collected and fixed in
4% formaldehyde for 24 h before embedding in paraffin. 4 .mu.m
thick sections are immunostained with anti-MnSOD antibody (Enzo
Life Sciences, Inc., Cat. No: ADI-SOD110). The sections are
deparaffinized and processed by heat-induced antigen retrieval
before incubation one hour with the anti-MnSOD primary antibody.
The anti-MnSOD antibody is detected by an anti-rabbit biotinylated
antibody (Vector Laboratories, Cat. No: BA-1100) amplified by
avidin-biotin peroxidase (Vector Laboratories, Cat. No: PK-6100).
The peroxidase is revealed with DAB substrate (Sigma, Cat. No:
D5905) and 0.025% hydrogen peroxide. The immunostained sections
counterstained with Gill's hematoxylin are then scanned (Nanozoomer
2.0HT, Hamamatsu) before quantification by image analysis (CaloPix
software, TRIBVN Healthcare). Data are expressed as percentage
MnSOD stained area per area of lung tissue.
[1199] Values for all mice from the same group are averaged. Data
are expressed as mean.+-.sem and are compared with a one-way ANOVA
followed by Dunnett multiple comparison post hoc test.
TABLE-US-00016 TABLE XV Type I collagen stained area fraction
[%]-Figure 15 Irradiated Irradiated Sham Irradiated nintedanib CpdA
7.2 16.2 9.3 nd 7.7 16.2 8.9 8.9 7.6 16.7 13.7 9.1 7.4 17.4 10.5
8.6 9.9 19.1 10.5 16.2 8.6 11.7 nd 14.7 9.1 10.8 7.6 nd 5.2 9.3 7.1
11.0 6.2 nd nd 13.0 5.6 nd 6.5 8.7 9.6 11.0 8.1 10.7 8.2 6.5 nd:
not determined
TABLE-US-00017 TABLE XVI MnSOD stained area fraction [%]-Figure 16
Irradiated Irradiated Sham Irradiated nintedanib CpdA 0.45 0.84
0.69 nd 0.20 1.35 0.92 0.99 0.30 1.29 0.53 0.57 0.43 0.84 1.11 0.26
0.62 1.79 1.19 0.31 0.81 0.75 nd 0.74 0.43 1.05 0.75 nd 0.36 0.95
0.25 0.39 0.13 nd nd 0.57 0.31 nd 0.50 0.57 2.14 0.79 0.71 0.79
0.62 0.66 nd: not determined
CLINICAL EXAMPLES
TABLE-US-00018 [1200] TABLE XVII List of abbreviations used herein:
Abbreviation Definition 6MWT 6-Minute Walk Test AE adverse event
ALAT Latin American Thoracic Association ALT alanine
aminotransferase AST aspartate aminotransferase ATS American
Thoracic Society DLCO diffusing capacity for the lungs for carbon
monoxide DNA deoxyribonucleic acid ECG electrocardiogram ERS
European Respiratory Society FEV1 forced expiratory volume in one
second FRI functional respiratory imaging FVC forced vital capacity
HRCT high-resolution computed tomography IMP investigational
medicinal product IPF idiopathic pulmonary fibrosis JRS Japanese
Respiratory Society SGRQ St. George's Respiratory Questionnaire
Example 1. Idiopathic Pulmonary Fibrosis (IPF) Clinical Study
[1201] The study of the current example is a randomized,
double-blind, parallel group, placebo-controlled, multicenter,
Phase II study to evaluate the efficacy, safety and tolerability of
Compound A in subjects with idiopathic pulmonary fibrosis (IPF).
The primary objective of this study is to evaluate the efficacy of
Compound A treatment in subjects with IPF on pulmonary function as
evaluated by FVC compared to placebo over 26 weeks.
1.1. Study Endpoints
[1202] Primary outcome measure is: [1203] Change from baseline in
FVC (mL) over 26 weeks compared to placebo.
[1204] Secondary outcome measures are: [1205] Safety and
tolerability changes over time (baseline to 26 weeks). [1206] Time
to any of major events (whichever occurs first) defined as: [1207]
Respiratory-related death [1208] First hospitalization (all-cause
and respiratory-related) [1209] Need to be placed on a lung
transplant list during the study [1210] Change from baseline 26
weeks in functional exercise capacity, assessed by the 6 MWT at
Week 26. [1211] Change from baseline until 26 weeks in quality of
life measures, assessed by the St. George's Respiratory
Questionnaire (SGRQ) total score and domains and proportion of SGRQ
responders. [1212] Concentrations of Compound A, nintedanib and
pirfenidone.
[1213] Other outcome measures are: [1214] Change from baseline in
FRI parameters, assessed by chest HRCT. [1215] Change in target
and/or disease specific biomarkers, in relation to genotype
subgroups in blood and/or clinical endpoints over time compared to
baseline
1.2. Study Interventions
[1216] The study provides for 2 types of interventions: [1217]
Drug: Compound A--100 mg administered orally once daily as 2
capsules of 50 mg with or without food [1218] Drug: Compound A
placebo--administered orally once daily as 2 capsules with or
without food
1.3. Study Arms
[1219] Study participants are randomized over 2 study arms:
[1220] 1. Experimental: Compound A: Compound A 100 mg, for 26
weeks
[1221] 2. Placebo Comparator: Placebo: Compound A placebo for 26
weeks
1.4. Eligibility Criteria
[1222] To be eligible, the subjects must meet the following
criteria: [1223] Males or females of non-child-bearing potential,
aged .gtoreq.40 years. [1224] A diagnosis of IPF within 3 years
prior to the screening visit as per American Thoracic Society
(ATS)/European Respiratory Society (ERS)/Japanese Respiratory
Society (JRS)/Latin American Thoracic Association (ALAT)
guidelines. [1225] Meeting all of the following criteria at
screening and during the screening period: [1226] FVC .gtoreq.50%
predicted of normal [1227] Disease progression in the last 9 months
prior to the screening period and at screening, defined as at least
one prescreening FVC value and screening value with a decline of
FVC (% predicted or mL), at the investigator's discretion [1228]
Diffusing capacity for the lungs for carbon monoxide (DLCO)
.gtoreq.30% predicted of normal (corrected for hemoglobin) [1229]
Ratio of forced expiratory volume in one second (FEV1) to FVC
.gtoreq.0.70
[1230] In a stable condition and suitable for study participation
based on the results of a medical history, physical examination,
vital signs, 12-lead ECG, and laboratory evaluation. Stable
condition is based on the clinical judgment of the investigator,
co-morbidities should be treated according to the local applicable
guidelines. Concomitant medication for comorbidities should be
stabilized from 4 weeks before screening and during the screening
period (stable defined as no change of dose or regimen). [1231]
Estimated minimum life expectancy of 12 months for non-IPF related
disease in the opinion of the investigator. [1232] Male subjects
with female partners of child bearing potential are willing to
comply with the contraceptive methods described in the protocol
(see Section 4.3.4.1) prior to the first dose of the IMP, during
the clinical study, and for at least 12 weeks after the last dose
of the IMP. [1233] Able to walk at least 150 meters during the 6
MWT at screening; without having a contraindication to perform the
6 MWT. [1234] Able to understand the importance of adherence, and
willing to comply to study treatment, study procedures and
requirements as per study protocol, including the concomitant
medication restrictions.
[1235] Key exclusion criteria: subjects meeting one or more of the
following criteria cannot be selected for this study: [1236] Known
hypersensitivity to any of the IMP ingredients or a history of a
significant allergic reaction to any drug as determined by the
investigator (e.g. anaphylaxis requiring hospitalization). [1237]
History of or a current immunosuppressive condition (e.g. human
immunodeficiency virus [HIV] infection, congenital, acquired,
medication induced). [1238] Positive serology for hepatitis B
(surface antigen and core antibody) or C (antibody), or any history
of hepatitis from any cause with the exception of hepatitis A.
[1239] History of malignancy within the past 5 years (except for
carcinoma in situ of the uterine cervix, basal cell carcinoma of
the skin that has been treated with no evidence of recurrence, and
prostate cancer medically managed through active surveillance or
watchful waiting, and squamous cell carcinoma of the skin if fully
resected). [1240] Acute IPF exacerbation within 3 months prior to
screening and during the screening period. [1241] Lower respiratory
tract infection requiring antibiotics within 4 weeks prior to
screening and/or during the screening period. [1242] Interstitial
lung disease associated with known primary diseases (e.g.
sarcoidosis, amyloidosis), exposures (e.g. radiation, silica,
asbestos, coal dust), and drugs (e.g. amiodarone). [1243] History
of lung volume reduction surgery or lung transplant. [1244]
Unstable cardiovascular, pulmonary (other than IPF) or other
disease within 6 months prior to screening or during the screening
period (e.g. coronary heart disease, heart failure, stroke). [1245]
Subject participating in a drug, device or biologic investigational
research study, concurrently with the current study, or within
5-half-lives of the agent (or within 8 weeks when half-life is
unknown) prior to screening, or prior participation in an
investigational drug antibody study within 6 months prior to
screening.
Final Remarks
[1246] It will be appreciated by those skilled in the art that the
foregoing descriptions are exemplary and explanatory in nature, and
intended to illustrate the invention and its preferred embodiments.
Through routine experimentation, an artisan will recognize apparent
modifications and variations that may be made without departing
from the spirit of the invention. All such modifications coming
within the scope of the appended claims are intended to be included
therein. Thus, the invention is intended to be defined not by the
above description, but by the following claims and their
equivalents.
[1247] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication are
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[1248] It should be understood that factors such as the
differential cell penetration capacity of the various compounds can
contribute to discrepancies between the activity of the compounds
in the in vitro biochemical and cellular assays.
[1249] At least some of the chemical names of compound of the
invention as given and set forth in this application, may have been
generated on an automated basis by use of a commercially available
chemical naming software program, and have not been independently
verified. Representative programs performing this function include
the Lexichem naming tool sold by Open Eye Software, Inc. and the
Autonom Software tool sold by MDL, Inc. In the instance where the
indicated chemical name and the depicted structure differ, the
depicted structure will control.
REFERENCES
[1250] Ashcroft, T., Simpson, J. M., Timbrell, V., 1988. Simple
method of estimating severity of pulmonary fibrosis on a numerical
scale. J. Clin. Pathol. 41, 467-470. [1251] Bickelhaupt, S., Erbel,
C., Timke, C., Wirkner, U., Dadrich, M., Flechsig, P., Tietz, A.,
Pfohler, J., Gross, W., Peschke, P., Hoeltgen, L., Katus, H. A.,
Grone, H.-J., Nicolay, N. H., Saffrich, R., Debus, J., Sternlicht,
M. D., Seeley, T. W., Lipson, K. E., Huber, P. E., 2017. Effects of
CTGF Blockade on Attenuation and Reversal of Radiation-Induced
Pulmonary Fibrosis. JNCI J. Natl. Cancer Inst. 109.
https://doi.org/10.1093/jnci/djw339 [1252] Brunnemer, E., Walscher,
J., Tenenbaum, S., Hausmanns, J., Schulze, K., Seiter, M., Heussel,
C. P., Warth, A., Herth, F. J. F., Kreuter, M., 2018. Real-World
Experience with Nintedanib in Patients with Idiopathic Pulmonary
Fibrosis. Respiration 95, 301-309.
https://doi.org/10.1159/000485933 [1253] Brunt, E. M., Kleiner, D.
E., Wilson, L. A., Belt, P., Neuschwander-Tetri, B. A., 2011. The
NAS and The Histopathologic Diagnosis in NAFLD: Distinct
Clinicopathologic Meanings. Hepatol. Baltim. Md 53, 810-820.
https://doi.org/10.1002/hep.24127 [1254] Day, C. P., James, O. F.
W., 1998. Hepatic steatosis: Innocent bystander or guilty party?
Hepatology 27, 1463-1466. https://doi.org/10.1002/hep.510270601
[1255] Devos, F. C., Maaske, A., Robichaud, A., Pollaris, L., Seys,
S., Lopez, C. A., Verbeken, E., Tenbusch, M., Lories, R., Nemery,
B., Hoet, P. H., Vanoirbeek, J. A., 2017. Forced expiration
measurements in mouse models of obstructive and restrictive lung
diseases. Respir. Res. 18, 123.
https://doi.org/10.1186/s12931-017-0610-1 [1256] Fujii, T., Fuchs,
B. C., Yamada, S., Lauwers, G. Y., Kulu, Y., Goodwin, J. M.,
Lanuti, M., Tanabe, K. K., 2010. Mouse model of carbon
tetrachloride induced liver fibrosis: Histopathological changes and
expression of CD133 and epidermal growth factor. BMC Gastroenterol.
10, 79. https://doi.org/10.1186/1471-230X-10-79 [1257] Inghilleri,
S., Morbini, P., Oggionni, T., Barni, S., Fenoglio, C., 2006. In
situ assessment of oxidant and nitrogenic stress in bleomycin
pulmonary fibrosis. Histochem. Cell Biol. 125, 661-669.
https://doi.org/10.1007/s00418-005-0116-7 [1258] Kleiner, D. E.,
Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings,
O. W., Ferrell, L. D., Liu, Y.-C., Torbenson, M. S., Unalp-Arida,
A., Yeh, M., McCullough, A. J., Sanyal, A. J., Nonalcoholic
Steatohepatitis Clinical Research Network, 2005. Design and
validation of a histological scoring system for nonalcoholic fatty
liver disease. Hepatol. Baltim. Md 41, 1313-1321.
https://doi.org/10.1002/hep.20701 [1259] Lancaster, L. H., Andrade,
J. A. de, Zibrak, J. D., Padilla, M. L., Albera, C., Nathan, S. D.,
Wijsenbeek, M. S., Stauffer, J. L., Kirchgaessler, K.-U., Costabel,
U., 2017. Pirfenidone safety and adverse event management in
idiopathic pulmonary fibrosis. Eur. Respir. Rev. 26, 170057.
https://doi.org/10.1183/16000617.0057-2017 [1260] Marra, F.,
DeFranco, R., Grappone, C., Milani, S., Pastacaldi, S., Pinzani,
M., Romanelli, R. G., Laffi, G., Gentilini, P., 1998. Increased
expression of monocyte chemotactic protein-1 during active hepatic
fibrogenesis: correlation with monocyte infiltration. Am. J.
Pathol. 152, 423-430. [1261] Matsuse, T., Teramoto, S., Katayama,
H., Sudo, E., Ekimoto, H., Mitsuhashi, H., Uejima, Y., Fukuchi, Y.,
Ouchi, Y., 1999. ICAM-1 mediates lung leukocyte recruitment but not
pulmonary fibrosis in a murine model of bleomycin-induced lung
injury. Eur. Respir. J. 13, 71-77. [1262] Matsuzawa, Y., Kawashima,
T., Kuwabara, R., Hayakawa, S., Irie, T., Yoshida, T., Rikitake,
H., Wakabayashi, T., Okada, N., Kawashima, K., Suzuki, Y., Shirai,
K., 2015. Change in serum marker of oxidative stress in the
progression of idiopathic pulmonary fibrosis. Pulm. Pharmacol.
Ther. 32, 1-6. https://doi.org/10.1016/j.pupt.2015.03.005 [1263]
Miyamoto, J., Hasegawa, S., Kasubuchi, M., Ichimura, A., Nakajima,
A., Kimura, I., 2016. Nutritional Signaling via Free Fatty Acid
Receptors. Int. J. Mol. Sci. 17.
https://doi.org/10.3390/ijms17040450 [1264] Nanthakumar, C. B.,
Hatley, R. J. D., Lemma, S., Gauldie, J., Marshall, R. P.,
Macdonald, S. J. F., 2015. Dissecting fibrosis: therapeutic
insights from the small-molecule toolbox. Nat. Rev. Drug Discov.
14, 693-720. https://doi.org/10.1038/nrd4592 [1265]
Neuschwander-Tetri, B. A., Caldwell, S. H., 2003. Nonalcoholic
steatohepatitis. Summary of an AASLD Single Topic Conference.
Hepatology 37, 1202-1219. https://doi.org/10.1053/jhep.2003.50193
[1266] Richeldi, L., du Bois, R. M., Raghu, G., Azuma, A., Brown,
K. K., Costabel, U., Cottin, V., Flaherty, K. R., Hansell, D. M.,
Inoue, Y., Kim, D. S., Kolb, M., Nicholson, A. G., Noble, P. W.,
Selman, M., Taniguchi, H., Brun, M., Le Maulf, F., Girard, M.,
Stowasser, S., Schlenker-Herceg, R., Disse, B., Collard, H. R.,
INPULSIS Trial Investigators, 2014. Efficacy and safety of
nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 370,
2071-2082. https://doi.org/10.1056/NEJMoa1402584 [1267] Richter,
K., Kietzmann, T., 2016. Reactive oxygen species and fibrosis:
further evidence of a significant liaison. Cell Tissue Res. 365,
591-605. https://doi.org/10.1007/s00441-016-2445-3 [1268]
Santhekadur, P. K., Kumar, D. P., Sanyal, A. J., 2017. Preclinical
Models of Nonalcoholic Fatty Liver Disease. J. Hepatol.
https://doi.org/10.1016/j.jhep.2017.10.031 [1269] Suzuki, M.,
Takaishi, S., Nagasaki, M., Onozawa, Y., Iino, I., Maeda, H.,
Komai, T., Oda, T., 2013. Medium-chain Fatty Acid-sensing Receptor,
GPR84, Is a Proinflammatory Receptor. J. Biol. Chem. 288,
10684-10691. https://doi.org/10.1074/jbc.M112.420042 [1270] Wang,
J., Wu, X., Simonavicius, N., Tian, H., Ling, L., 2006.
Medium-chain Fatty Acids as Ligands for Orphan G Protein-coupled
Receptor GPR84. J. Biol. Chem. 281, 34457-34464.
https://doi.org/10.1074/jbc.M608019200 [1271] Wittenberger, T.,
Schaller, H. C., Hellebrand, S., 2001. An expressed sequence tag
(EST) data mining strategy succeeding in the discovery of new
G-protein coupled receptors. J. Mol. Biol. 307, 799-813.
https://doi.org/10.1006/jmbi.2001.4520 [1272] Yousefi, S., Cooper,
P. R., Potter, S. L., Mueck, B., Jarai, G., 2001. Cloning and
expression analysis of a novel G-protein-coupled receptor
selectively expressed on granulocytes. J. Leukoc. Biol. 69,
1045-1052. [1273] Zimmermann, H. W., Seidler, S., Nattermann, J.,
Gassler, N., Hellerbrand, C., Zernecke, A., Tischendorf, J. J. W.,
Luedde, T., Weiskirchen, R., Trautwein, C., Tacke, F., 2010.
Functional Contribution of Elevated Circulating and Hepatic
Non-Classical CD14+CD16+ Monocytes to Inflammation and Human Liver
Fibrosis. PLOS ONE 5, e11049.
https://doi.org/10.1371/journal.pone.0011049
* * * * *
References